Placebo-Controlled Trials

Citation and Study InformationEligibility, Interventions, OutcomesResults, Adverse Events, and Withdrawals
Armenteros et al. 200777

ADHD

Risperidone

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 4

Age: Not reported

Sex: 80-99% Male

Race: Caucasian, African Ancestry, Other-NOS

Screened: NR
Eligible: NR
Entering: 25
Withdrawn: 2
Lost to follow-up: 0
Analyzed: 23

Method of AE assessment: Monitored
Inclusion criteria:
ADHD, treated constant does of stimulant for 3 weeks prior, aggressive behavior, AQPA of <= 0, CGI-S >= 4, IQ >=75, normal physical and labs

Exclusion criteria:
Substance use disorder, unstable illness, history of intolerance or failure to respond to risperidone, suicidal or homicidal

Interventions:
Placebo for 28 days
 vs
Risperidone 0.5-2 mg/days flexible dose for 28 days

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety

Timing of outcome assessment: 7, 14, 21, 28 days
Results:
ADHD: Change in CAS-P (improvement = >=30%) at 4 weeks:
Risperidone vs Placebo - RR = 1.19 ( 0.89 , 1.59 )

Adverse Events:
Placebo vs Risperidone
Abdominal Pain: 7.7%(1/13) vs 25.0%(3/12)
Agitation: 0.0%(0/13) vs 8.3%(1/12)
At Least One Adverse Event: 76.9%(10/13) vs 58.3%(7/12)
Increased Appetite: 0.0%(0/13) vs 8.3%(1/12)
Somnolence: 15.4%(2/13) vs 8.3%(1/12)
Vomiting: 23.1%(3/13) vs 16.7%(2/12)

Withdrawals:
Placebo vs Risperidone
Withdrawals:7.7%(1/13) vs 8.3%(1/12)
Withdrawals Due To Adverse Events:0.0%(0/13) vs 0.0%(0/12)
Tramontina et al. 200979

ADHD

Aripiprazole

Location: Latin America

Trial: Not reported

Funding source: Government, Industry

Design: RCT only

Setting: Single setting

Jadad: 5

Age: Mean: 12

Sex: Mixed

Race: Caucasian, Other-NOS

Screened: 710
Eligible: 43
Entering: 43
Withdrawn: 2
Lost to follow-up: 0
Analyzed: 41

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
Age 8-17, bipolar I or II disorder comorbid ADHD acutely manic or mixed state, clear reports of ADHD symptom onset preceding any mood symptomatology

Exclusion criteria:
Estimated IQ < 70, use of any medication 4 weeks prior to entering the study, pervasive developmental disorder, schizophrenia, substance abuse, suicide risk, previous use of aripiprazole, pregnancy, chronic diseases

Interventions:
Placebo 2-20 mg/days flexible dose for 6 weeks
 vs
Aripiprazole 2-20 mg/days flexible dose for 6 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety

Timing of outcome assessment: 7, 14, 21, 28, 35, 42 days
Results:
ADHD: Change in SNAP-IV Total Score (Total Score) at 6 weeks:
Aripiprazole vs Placebo - WMD = 0.05 ( -0.34 , 0.44 )

Adverse Events:
Excluded from analysis:
Reflexes Change: 5.6%(1/18) vs 0.0%(0/25)
Rhinitis: 27.8%(5/18) vs 64.0%(16/25)
Sialorrhea: 72.2%(13/18) vs 52.0%(13/25)
Skin Rash: 0.0%(0/18) vs 4.0%(1/25)
Slowness Of Thought: 5.6%(1/18) vs 12.0%(3/25)
Somnolence: 94.4%(17/18) vs 76.0%(19/25)
Suicidal Ideation: 27.8%(5/18) vs 20.0%(5/25)
Sweating: 55.6%(10/18) vs 44.0%(11/25)
Tiredness: 83.3%(15/18) vs 56.0%(14/25)
Tremors: 44.4%(8/18) vs 32.0%(8/25)
Vomiting: 27.8%(5/18) vs 20.0%(5/25)

Withdrawals:
Aripiprazole vs Placebo
Withdrawals:5.6%(1/18) vs 4.0%(1/25)
Withdrawals Due To Adverse Events:5.6%(1/18) vs 0.0%(0/25)
Bandelow et al. 200988

Anxiety

Quetiapine

Location: Canada, Western Europe, Eastern Europe, Latin America, South Africa

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 5

Age: Mean: 18

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: 1054
Eligible: NR
Entering: 873
Withdrawn: 188
Lost to follow-up: 9
Analyzed: 473

Method of AE assessment: Monitored
Inclusion criteria:
18-65 years old, diagnosed GAD, HAM-A total score >= 20 with item 1 and 2 scores >= 2, MADRS total score <= 16, CGI-S score >=4 at enrollment and randomization.

Exclusion criteria:
Diagnosis of any DSM-IV-TR Axis I disorder other than GAD within 6 months or DSM -IV-TR Axis II disorder, MADRS item 10 score >=4, suicide attempt, alcohol abuse

Interventions:
Placebo for 8 weeks
 vs
Quetiapine 50-150 mg/days fixed titration schedule for 8 weeks
 vs
Quetiapine 50 mg/days fixed single dose for 8 weeks
 vs
Paroxetine 20 mg/days fixed single dose for 8 weeks

Run-in/wash-out period:
Wash-out: No drug for 1-4 week(s). Eligible patents were randomized.

Comorbidities:
None

Timing of outcome assessment: 1, 4, 7, 14, 21, 28, 42, 56 days
Results:
Anxiety: Change in HAM-A (% Responder) at 8 weeks:
Quetiapine vs Placebo - RR = 1.36 (1.17 , 1.59)

Adverse Events:
Paroxetine vs Placebo vs Quetiapine 150 mg vs Quetiapine 50mg
>=7% Increase In Body Weight At End of Treatment: 4.6%(10/217) vs 2.3%(5/217) vs 6.9%(15/218) vs 4.5%(10/221)
Anxiety: 5.1%(11/217) vs 0.5%(1/217) vs 1.4%(3/218) vs 1.4%(3/221)
Constipation: 2.8%(6/217) vs 1.4%(3/217) vs 6.0%(13/218) vs 4.5%(10/221)
Diarrhea: 5.5%(12/217) vs 4.6%(10/217) vs 3.7%(8/218) vs 3.2%(7/221)
Dizziness: 13.4%(29/217) vs 6.0%(13/217) vs 15.6%(34/218) vs 11.8%(26/221)
Dry Mouth: 9.7%(21/217) vs 6.0%(13/217) vs 25.7%(56/218) vs 15.8%(35/221)
Extrapyramidal Adverse Events: 8.3%(18/217) vs 1.8%(4/217) vs 5.0%(11/218) vs 6.8%(15/221)
Fasting HDL Cholesterol =40 mg/dL At End of Treatment: 1.4%(3/217) vs 5.5%(12/217) vs 3.7%(8/218) vs 2.7%(6/221)
Fasting Total Cholesterol =240 mg/dL At End of Treatment: 6.5%(14/217) vs 3.2%(7/217) vs 5.0%(11/218) vs 4.1%(9/221)
Fasting Triglycerides >=200 mg/dL At End of Treatment: 3.7%(8/217) vs 2.8%(6/217) vs 8.3%(18/218) vs 3.2%(7/221)
Fatigue: 9.2%(20/217) vs 3.7%(8/217) vs 16.5%(36/218) vs 14.9%(33/221)
Headache: 17.1%(37/217) vs 18.0%(39/217) vs 12.4%(27/218) vs 16.3%(36/221)
Insomnia: 13.4%(29/217) vs 6.5%(14/217) vs 8.7%(19/218) vs 7.7%(17/221)
Nasopharyngitis: 6.0%(13/217) vs 3.7%(8/217) vs 2.3%(5/218) vs 3.2%(7/221)
Nausea: 24.4%(53/217) vs 9.2%(20/217) vs 11.9%(26/218) vs 11.3%(25/221)
Overall Incidence Of Adverse Events: 72.8%(158/217) vs 55.8%(121/217) vs 76.1%(166/218) vs 71.0%(157/221)
Sedation: 2.3%(5/217) vs 0.5%(1/217) vs 8.3%(18/218) vs 6.3%(14/221)
Sexual Dysfunction: 7.4%(16/217) vs 2.3%(5/217) vs 1.8%(4/218) vs 0.9%(2/221)
Somnolence: 11.1%(24/217) vs 4.6%(10/217) vs 25.2%(55/218) vs 21.7%(48/221)
Treatment-Related Adverse Events: 58.5%(127/217) vs 34.6%(75/217) vs 65.6%(143/218) vs 58.8%(130/221)
Paroxetine vs Placebo vs Quetiapine 50mg
Fasting LDL Cholesterol = 160 mg/dL At End of Treatment: 6.5%(14/217) vs 3.7%(8/217) vs 3.2%(7/221)
Quetiapine 150 mg
Fasting LDL Cholesterol = >160 mg/dL At End of Treatment: 4.1%(9/218)
Quetiapine 50mg vs Quetiapine 150 mg vs Placebo vs Paroxetine
Fasting Glucose =>126 mg/dL At End of Treatment: 0.9%(2/221) vs 0.5%(1/218) vs 1.4%(3/217) vs 1.4%(3/217)

Withdrawals:
Paroxetine vs Placebo vs Quetiapine 150 mg vs Quetiapine 50mg
Withdrawals:45.2%(98/217) vs 41.9%(91/217) vs 48.2%(105/218) vs 48.0%(106/221)
Withdrawals Due To Adverse Events:7.8%(17/217) vs 4.1%(9/217) vs 16.1%(35/218) vs 11.8%(26/221)
Barnett et al. 200283

Anxiety

Olanzapine

Location: Not reported

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Mean: 18

Sex:

Race: Not reported

Screened: NR
Eligible: 12
Entering: 12
Withdrawn: 2
Lost to follow-up: 3
Analyzed: 7

Method of AE assessment: Monitored
Inclusion criteria:
18-65, social anxiety disorder, DSM-IV of social phobia of, brief social phobia scale (BSPS) >= 20

Exclusion criteria:
NR

Interventions:
Placebo 5 mg/days flexible dose for 8 weeks
 vs
Olanzapine 5-20 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Run-in: Placebo for 1 week(s).

Comorbidities:
None

Timing of outcome assessment: 14, 21, 28, 42, 56 days
Results:
Anxiety: Change in Brief Social Phobia Scale at 8 weeks:
Olanzapine vs Placebo - WMD = -10.60 ( -26.09 , 4.89 )

Adverse Events:
Olanzapine vs Placebo
Constipation: 14.3%(1/7) vs 0.0%(0/5)
Drowsiness: 57.1%(4/7) vs 0.0%(0/5)
Dry Mouth: 42.9%(3/7) vs 0.0%(0/5)
Headache: 0.0%(0/7) vs 20.0%(1/5)
Significant Changes On The BAS Or AIMS: 0.0%(0/7) vs 0.0%(0/5)
Thirst: 14.3%(1/7) vs 0.0%(0/5)
Weight Gain: 0.0%(0/7) vs 20.0%(1/5)

Withdrawals:
Olanzapine vs Placebo
Withdrawals:42.9%(3/7) vs 40.0%(2/5)
Withdrawals Due To Adverse Events:14.3%(1/7) vs 20.0%(1/5)
Brawman-Mintzer et al. 200598

Anxiety

Risperidone

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Not reported

Sex: 80-99% Female

Race: Caucasian

Screened: NR
Eligible: NR
Entering: 40
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 31

Method of AE assessment: Monitored
Inclusion criteria:
Age >=18, GAD, HAM-A >=18, CGI-S >=4, Covi > Raskin score despite adequate treatment >= 4 weeks

Exclusion criteria:
MDD 1 month prior, substance use disorder 6 month prior, bipolar or psychotic disorder

Interventions:
Placebo for 5 weeks
 vs
Risperidone 0.5-1.5 mg/days flexible dose for 5 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety

Timing of outcome assessment: 7, 14, 21, 28, 35 days
Results:
Anxiety: Change in HAM-A (Total Score) at 5 weeks:
Risperidone vs Placebo - WMD = -3.60 ( -6.88 , -0.32 )

Adverse Events:
Placebo vs Risperidone
Blurred Vision: 0.0%(0/20) vs 15.0%(3/20)
Dizziness: 15.0%(3/20) vs 20.0%(4/20)
Required Adjunctive Treatment With Anticholinergic Agents: 0.0%(0/20) vs 0.0%(0/20)
Somnolence: 15.0%(3/20) vs 45.0%(9/20)

Withdrawals:
Placebo vs Risperidone
Withdrawals:20.0%(4/20) vs 25.0%(5/20)
Withdrawals Due To Adverse Events:5.0%(1/20) vs 15.0%(3/20)
Donahue et al. 200995

Anxiety

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Single setting

Jadad: 3

Age: Mean: 18

Sex: Mixed

Race: Not reported

Screened: 81
Eligible: 44
Entering: 24
Withdrawn: 3
Lost to follow-up: 1
Analyzed: NR

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
Diagnosis of SAD and clinically significant public speaking

Exclusion criteria:
Current contraindications or a history of sensitivity to quetiapine, current regular use of benzodiazepine, tranquilizer or antipsychotic medications, active psychotic/manic/depressed episode, unstable diabetes mellitus, heart disease, neurologic disorder, liver disease

Interventions:
Placebo for 1 hours
 vs
Quetiapine 25 mg/days fixed single dose for 1 hours

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 1, 2, 3, 4 minutes
Results:
Anxiety: Cross over study

Adverse Events:
Excluded from analysis: Sample size by group not reported
Hirschfeld et al. 200692

Anxiety

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Mean: 37

Sex: Mixed

Race: Not reported

Screened: 838
Eligible: 542
Entering: 542
Withdrawn: 216
Lost to follow-up: NR
Analyzed: 326

Method of AE assessment: Not reported
Inclusion criteria:
Outpatients aged 18-65. bipolar I or II disorder, current episode depressed, with a duration between 4 weeks and1 year, HAM-D score >= 2, young mania rating scale score <= 12.

Exclusion criteria:
Diagnosed Axis I disorder other than bipolar disorder within 6 months, history of nonresponse to adequate trial during current episode, substance abuse within 12 months.

Interventions:
Placebo for 8 weeks
 vs
Quetiapine 50-300 mg/days frequency not reported for 8 weeks
 vs
Quetiapine 50-600 mg/days frequency not reported for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56 days
Results:
Anxiety: Insufficient data to calculate an effect size
Pandina et al. 200799

Anxiety

Risperidone

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 5

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic, Other-NOS

Screened: 453
Eligible: 417
Entering: 417
Withdrawn: 76
Lost to follow-up: 11
Analyzed: 303

Method of AE assessment: Monitored
Inclusion criteria:
15-65, GAD, CGI-S >=4, antidepressant, benzodiazepine, buspirone or a combination of an antidepressants plus benzodiazepine or buspirone for at least 8 weeks prior and stable × 4 weeks

Exclusion criteria:
Pregnancy, suicide risk, serious illness, active substance abuse disorder, history of clozapine, other agents to manage anxiety, other axis I

Interventions:
Placebo 0.25-2 mg/days flexible dose for 4 weeks
 vs
Risperidone 0.25-2 mg/days flexible dose for 4 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42 days
Results:
Anxiety: Change in HAM-A (% Responder) at 6 weeks:
Risperidone vs Placebo - RR = 0.99 ( 0.78 , 1.25 )

Withdrawals:
Placebo augmentation vs Risperidone augmentation
Withdrawals:21.1%(41/194) vs 23.5%(46/196)
Withdrawals Due To Adverse Events:5.2%(10/194) vs 10.7%(21/196)
Pollack et al. 200684

Anxiety

Olanzapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 2

Age: Not reported

Sex: Mixed

Race: Not reported

Screened: 46
Eligible: 24
Entering: 24
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 17

Method of AE assessment: Monitored
Inclusion criteria:
18-72 DSM-IV generalized anxiety disorder comorbid depression on dysthymia and other anxiety disorders except for PTSD and OCD if GAD was considered primary by the clinician and patient based on disorder severity and associated distress.

Exclusion criteria:
Bipolar or psychotic disorders, alcohol or substance abuse or dependence within the last 6 months or those receiving concurrent structured psychotherapies directed at the GAD.

Interventions:
Placebo for 6 weeks
 vs
Olanzapine 2.5-20 mg/days flexible dose for 6 weeks

Run-in/wash-out period:
Run-in: Fluoxetine for 6 week(s).
Symptomatic patients were randomized.

Comorbidities:
Depression

Timing of outcome assessment: 42, 84 days
Results:
Anxiety: Change in HAM-A (% Responder) at 6 weeks:
Olanzapine vs Placebo - RR = 6.67 ( 0.93 , 47.59 )

Adverse Events:
Olanzapine vs Placebo
At Least One AE: 100.0%(12/12) vs 100.0%(12/12)
Gained =7% Of Their Body Weight: 16.7%(2/12) vs 0.0%(0/12)
Gastrointestinal Distress: 33.3%(4/12) vs 25.0%(3/12)
Increased Appetite: 25.0%(3/12) vs 16.7%(2/12)
Sedation: 91.7%(11/12) vs 41.7%(5/12)
Sexual Dysfunction: 16.7%(2/12) vs 25.0%(3/12)
Weight Gain: 58.3%(7/12) vs 16.7%(2/12)

Withdrawals:
Olanzapine vs Placebo
Withdrawals:41.7%(5/12) vs 16.7%(2/12)
Withdrawals Due To Adverse Events:33.3%(4/12) vs 8.3%(1/12)
Withdrawals Due to Adverse Events: Sedation:33.3%(4/12) vs 8.3%(1/12)
Simon et al. 200885

Anxiety

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry

Screened: 101
Eligible: 24
Entering: 22
Withdrawn: 6
Lost to follow-up: NR
Analyzed: 16

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
Did not receive remission of GAD in >=18

Exclusion criteria:
<= 7 HAM-A, pregnant / lactating, MD, dysthymia, panic, social phobia, bipolar, psychotic, PTSD, OCD, alcohol or substance abuse / dependence 6 month prior, unstable illness

Interventions:
Placebo for 8 weeks
 vs
Quetiapine 25-400 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Run-in: SRI monotherapy for 10 week(s).
Non-responders were randomized.

Comorbidities:
Anxiety, Depression

Timing of outcome assessment: 56 days
Results:
Anxiety: Change in HAM-A (Total Score) at 8 weeks:
Quetiapine vs Placebo - WMD = -2.36 ( -7.99 , 3.27 )

Adverse Events:
Placebo+Paroxetine vs Placebo+Paroxetine vs Quetiapine+Paroxetine vs Quetiapine+Paroxetine
Diarrhea: 0.0%(0/11) vs 18.2%(2/11) vs 27.3%(3/11) vs 0.0%(0/11)
Placebo+Paroxetine vs Quetiapine+Paroxetine
Constipation: 18.2%(2/11) vs 0.0%(0/11)
Dry Mouth: 0.0%(0/11) vs 27.3%(3/11)
Insomnia: 27.3%(3/11) vs 0.0%(0/11)
Nausea: 0.0%(0/11) vs 18.2%(2/11)
Sedation: 0.0%(0/11) vs 54.5%(6/11)
Sexual Dysfunction: 18.2%(2/11) vs 18.2%(2/11)
Vivid Dreams: 27.3%(3/11) vs 0.0%(0/11)
Weight Gain: 18.2%(2/11) vs 0.0%(0/11)

Withdrawals:
Placebo+Paroxetine vs Quetiapine+Paroxetine
Withdrawals:9.1%(1/11) vs 45.5%(5/11)
Withdrawals Due To Adverse Events:9.1%(1/11) vs 36.4%(4/11)
Vaishnavi et al. 200789

Anxiety

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 4

Age: Not reported

Sex: Mixed

Race: Caucasian, Other-NOS

Screened: NR
Eligible: NR
Entering: 15
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
18-65, outpatients, social anxiety disorder, CGI-S>=4, –BSPS>=20, negative pregnancy test

Exclusion criteria:
Bipolar, schizophrenia or other psychotic disorder, mental retardation, pervasive developmental disorder, cognitive disorder due to general medical condition, other anxiety disorder, MDD, history of substance dependence 6 month prior, suicide risk, medical illness, psychotropic medication and history of hypersensitivity to quetiapine

Interventions:
Placebo 50-400 mg/days flexible dose for 8 weeks
 vs
Quetiapine 50-400 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 21, 35, 56 days
Results:
Anxiety: Change in BSPS at 8 weeks:
Quetiapine vs Placebo - WMD = 30.50 ( 16.86 , 44.14 )

Adverse Events:
Quetiapine vs Placebo
Blurred Vision: 10.0%(1/10) vs 0.0%(0/5)
Dizziness: 30.0%(3/10) vs 0.0%(0/5)
Drowsiness: 50.0%(5/10) vs 0.0%(0/5)
Headache: 10.0%(1/10) vs 0.0%(0/5)
Nausea: 20.0%(2/10) vs 0.0%(0/5)
Sweating: 10.0%(1/10) vs 0.0%(0/5)
Swelling: 10.0%(1/10) vs 0.0%(0/5)
Thirst: 10.0%(1/10) vs 0.0%(0/5)
Tinnitus: 10.0%(1/10) vs 0.0%(0/5)
Merideth et al. 200887

Anxiety

Quetiapine

Location: Not reported

Trial: D1448C00010

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 2

Age: Not reported

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: 854
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
DSM-IV diagnosis of GAD, HAM-A total score >=20 with item 1 and item 2 scores >=2, CGI- S >=4, MADRS <=16

Exclusion criteria:
Not reported

Interventions:
Placebo for 8 weeks
 vs
Escitalopram 10 mg/days frequency not reported for 8 weeks
 vs
Quetiapine 150 mg/days frequency not reported for 8 weeks
 vs
Quetiapine 300 mg/days frequency not reported for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 4, 56 days
Results:
Anxiety: Change in HAM-A (% Responder) at 8 weeks:
Quetiapine vs Placebo - RR = 1.46 ( 1.21 , 1.76 )
Joyce et al. 200894

Anxiety

Quetiapine

Location: US

Trial: D1448C00009

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 2

Age: Not reported

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: 710
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
Not reported

Exclusion criteria:
Not reported

Interventions:
Placebo for 8 weeks
 vs
Quetiapine 50 mg/days frequency not reported for 8 weeks
 vs
Quetiapine 150 mg/days frequency not reported for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 56 days
Results:
Anxiety: Change in HAM-A (% Responder) at 8 weeks:
Quetiapine vs Placebo - RR = 1.02 ( 0.85 , 1.21 )
Lohoff et al. 2010100

Anxiety

Ziprasidone

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Single setting

Jadad: 4

Age: Not reported

Sex:

Race: Not reported

Screened: 73
Eligible: NR
Entering: 62
Withdrawn: 12
Lost to follow-up: 3
Analyzed: 47

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
>18 years old, meet DSM-IV criteria for GAD, have treatment failure of >= 1 adequate trial of an SSRI, SNRI, BZ, or combination HAM-A total score >= 16, CGI-S score >=4

Exclusion criteria:
Had a history of mania, bipolar disorder, schizophrenia, other psychotic disorders, had a history within 6 months of panic disorder, PTSD, major depression, OCD, social phobia, acute stress disorder, substance abuse, or other psychiatric diagnoses that may interfere with assessment, had clinical significant abnormalities, pregnant

Interventions:
Placebo 20-80 mg/days flexible dose for 8 weeks
 vs
Ziprasidone 20-80 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56 days
Results:
Anxiety: Change in HAM-A (Total Score) at 8 weeks:
Ziprasidone vs Placebo - WMD = -2.80 ( -10.71 , 5.11 )

Anxiety: Change in HAM-A (Total Score) at 8 weeks:
Ziprasidone vs Placebo - WMD = 2.83 ( -2.26 , 7.92 )

Adverse Events:
Placebo vs Ziprasidone
Any Adverse Event: 85.7%(18/21) vs 87.8%(36/41)
Blurred Vision: 0.0%(0/21) vs 4.9%(2/41)
Constipation: 14.3%(3/21) vs 9.8%(4/41)
Depression: 0.0%(0/21) vs 9.8%(4/41)
Dermatitis: 9.5%(2/21) vs 0.0%(0/41)
Diarrhea: 14.3%(3/21) vs 7.3%(3/41)
Dizziness: 4.8%(1/21) vs 17.1%(7/41)
Drowsiness: 28.6%(6/21) vs 51.2%(21/41)
Dry Mouth: 9.5%(2/21) vs 31.7%(13/41)
Excitement: 4.8%(1/21) vs 14.6%(6/41)
Headaches: 28.6%(6/21) vs 19.5%(8/41)
Insomnia: 9.5%(2/21) vs 29.3%(12/41)
Nausea: 9.5%(2/21) vs 14.6%(6/41)
Stimulation: 19.0%(4/21) vs 43.9%(18/41)
Tacchycardia: 0.0%(0/21) vs 2.4%(1/41)
Vivid Dreams: 0.0%(0/21) vs 4.9%(2/41)
Weight Gain: 9.5%(2/21) vs 7.3%(3/41)
Weight Loss: 4.8%(1/21) vs 2.4%(1/41)

Withdrawals:
Placebo vs Ziprasidone
Withdrawals:9.5%(2/21) vs 31.7%(13/41)
Withdrawals Due To Adverse Events:0.0%(0/21) vs 12.2%(5/41)
Katzman et al. 201193

Anxiety

Quetiapine

Location: US, Canada, Western Europe, Eastern Europe, Australia/New Zealand, Asia

Trial: platinum (D1448C00012)

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 4

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: NR
Eligible: NR
Entering: 432
Withdrawn: 53
Lost to follow-up: 14
Analyzed: 365

Method of AE assessment: Monitored, reported spontaneously by patient
Inclusion criteria:
18-65 years old, DSM-IV-TR diagnosis of GAD, HAM-A total >= 20, HAM-A item 1 and 2 >= 2, CGI-S >= 4

Exclusion criteria:
MADRS total >= 17, DSM-IV Axis 1 disorder other than GAD within 6 months, schizophrenia and other psychotic disorders, substance abuse

Interventions:
Placebo 165.1 mg/days flexible dose for 69 days
 vs
Quetiapine 162.8 (50-300) mg/days flexible dose for 107 days

Run-in/wash-out period:
Run-in: Quetiapine XR for 4-8 week(s).
Patients who met the study criteria were randomized.
In Wash-out: Psychotropics for 28 day(s) were randomized.

Comorbidities:
None

Timing of outcome assessment: 7, 14, 28, 56, 364 days
Results:
Anxiety: Change in HAM-A (Mean Change) at 12 weeks:
Quetiapine (varied) vs Placebo - WMD = -2.04 ( -2.09 , -1.99 )

Adverse Events:
Placebo
Syncope: 0.5%(1/216)
Placebo vs Quetiapine XR
“treatment-Related Aes”: 22.2%(48/216) vs 24.1%(52/216)
Aes “potentially Related To Qt Prolongation Or Agranulocytosis”: 0.0%(0/216) vs 0.0%(0/216)
Fatal Saes: 0.0%(0/216) vs 0.0%(0/216)
Insomnia: 13.9%(30/216) vs 3.2%(7/216)
Neutropenia “possibly Tx Related”: 0.0%(0/216) vs 0.5%(1/216)
Non-Fatal Saes: 1.4%(3/216) vs 1.4%(3/216)
Saes Reported By >1 Pt: 0.0%(0/216) vs 0.0%(0/216)
Sedation, Mild To Moderate In Intensity: 0.0%(0/216) vs 2.3%(5/216)
Somnolence, Mild To Moderate In Intensity: 0.0%(0/216) vs 0.9%(2/216)
Worsening In Aims Total Score (Items 1-7): 5.1%(11/216) vs 2.3%(5/216)
Worsening In Bars Global Assessment Score During Randomized Period: 4.6%(10/216) vs 2.8%(6/216)
Worsening In Sas Total Score During Randomized Period: 7.9%(17/216) vs 5.6%(12/216)
Quetiapine XR
Syncope During The Randomized Period: 0.0%(0/216)

Withdrawals:
Placebo vs Placebo vs Quetiapine XR vs Quetiapine XR
Headache Leading To Withdrawal:12.5%(27/216) vs 0.5%(1/216) vs 8.8%(19/216) vs 0.0%(0/216)
Placebo vs Quetiapine XR
Akathisia, Not Serious, Did Not Lead To Withdrawal During Randomized Period:0.9%(2/216) vs 0.5%(1/216)
Alanine Aminotransferase Increased Leading To Withdrawal:0.5%(1/216) vs 0.0%(0/216)
Any Ae Leading To Withdrawal:51.4%(111/216) vs 51.9%(112/216)
Aspartate Aminotransferase Increased Leading To Withdrawal:0.5%(1/216) vs 0.0%(0/216)
Bladder Cancer Leading To Withdrawal:0.0%(0/216) vs 0.5%(1/216)
Epilepsy Leading To Withdrawal:0.0%(0/216) vs 0.5%(1/216)
Fatigue Leading To Withdrawal:0.5%(1/216) vs 0.0%(0/216)
Glycosylated Hemoglobin Increased Leading To Withdrawal:0.0%(0/216) vs 0.5%(1/216)
Insomnia Leading To Withdrawal:1.9%(4/216) vs 0.0%(0/216)
Nasopharyngitis Leading To Withdrawal:3.2%(7/216) vs 5.1%(11/216)
Nausea Leading To Withdrawal:14.8%(32/216) vs 3.7%(8/216)
Non-Fatal Saes Leading To Withdrawal:0.5%(1/216) vs 0.9%(2/216)
Pancreatitis Leading To Withdrawal:0.5%(1/216) vs 0.0%(0/216)
Pruritus Generalized Leading To Withdrawal:0.5%(1/216) vs 0.0%(0/216)
Restlessness, Not Serious, Did Not Lead To Withdrawal During Randomized Period:0.0%(0/216) vs 1.9%(4/216)
Somnolence Leading To Withdrawal:0.0%(0/216) vs 0.5%(1/216)
Suicidal Behavior Leading To Withdrawal:0.0%(0/216) vs 0.5%(1/216)
Tremor, Not Serious, Did Not Lead To Withdrawal During Randomized Period:0.5%(1/216) vs 0.9%(2/216)
Withdrawals:55.1%(119/216) vs 25.0%(54/216)
Withdrawals Due To Adverse Events:2.8%(6/216) vs 2.3%(5/216)
Altamura et al. 201190

Anxiety

Quetiapine

Location: Western Europe

Trial: Not reported

Funding source: Not reported

Design: RCT only

Setting: Single setting

Jadad: 3

Age: Not reported

Sex: Mixed

Race: Not reported

Screened: NR
Eligible: NR
Entering: 20
Withdrawn: 0
Lost to follow-up: 0
Analyzed: 20

Method of AE assessment: Not reported
Inclusion criteria:
GAD per DSM-IV and SCID

Exclusion criteria:
Concomitant treatment with benzodiazepines, severe medical disease, pregnancy, breast feeding

Interventions:
Placebo for 8 weeks
 vs
Quetiapine 50 (25-150) mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
Depression, OCD, Personality Disorder

Timing of outcome assessment: 56 days
Results:
Anxiety: Change in HAM-A (% Responder) at 8 weeks:
Quetiapine Augmentation vs Placebo - RR = 1.13 ( 0.88 , 1.45 )
Mintzer et al. 2007107

Dementia/Agitation

Aripiprazole

Location: US, Canada, Australia/New Zealand, Latin America, South Africa

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center, Long-term care facilities

Jadad: 3

Age: Mean: 56

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic, Asian/Pacific Islander, Other-NOS

Screened: 654
Eligible: 487
Entering: 487
Withdrawn: 203
Lost to follow-up: 0
Analyzed: 284

Method of AE assessment: Monitored, other
Inclusion criteria:
Diagnosed with AD and delusions / hallucinations. Institutionalized, capable of self-locomotion, MMSE 6-22. NPI-NH score >=6

Exclusion criteria:
Delirium, amnestic disorder, bipolar disorder, schizophrenia, mood disorder, non-AD, depression with hallucinations / delusions, history of refractoriness to antipsychotics, suicidal ideation, previous participation in aripiprazole trials, pregnancy.

Interventions:
Placebo for 10 weeks
 vs
Aripiprazole 2 mg/days fixed single dose for 10 weeks
 vs
Aripiprazole 5 mg/days fixed single dose for 10 weeks
 vs
Aripiprazole 5-10 mg/days fixed single dose for 10 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 42, 56, 70 days
Results:
Dementia: Change in CMAI (Agitation) at 10 weeks:
Placebo vs Aripriprazole (all doses combined) - SMD = 0.31 ( 0.10 , 0.52 )

Dementia: Change in NPI psy (Psychosis) at 10 weeks:
Placebo vs Aripriprazole (all doses combined) - SMD = 0.24 ( 0.03 , 0.45 )

Dementia: Change in NPI total (Total) at 10 weeks:
Placebo vs Aripriprazole (all doses combined) - SMD = 0.16 ( -0.05 , 0.37 )

Adverse Events:
Aripiprazole 10 mg vs Aripiprazole 10 mg vs Aripiprazole 2 mg vs Aripiprazole 2 mg vs Aripiprazole 5 mg vs Aripiprazole 5 mg vs Placebo vs Placebo
Infection: 5.6%(7/126) vs 5.6%(7/126) vs 7.6%(9/118) vs 7.6%(9/118) vs 4.9%(6/122) vs 4.9%(6/122) vs 4.1%(5/121) vs 4.1%(5/121)
Aripiprazole 10 mg vs Aripiprazole 2 mg vs Aripiprazole 5 mg vs Placebo
Abdominal Pain: 4.0%(5/126) vs 2.5%(3/118) vs 6.6%(8/122) vs 3.3%(4/121)
Abnormal Gait: 4.0%(5/126) vs 1.7%(2/118) vs 7.4%(9/122) vs 0.8%(1/121)
Accidental Injury: 19.8%(25/126) vs 29.7%(35/118) vs 23.8%(29/122) vs 19.0%(23/121)
Agitation: 10.3%(13/126) vs 11.0%(13/118) vs 7.4%(9/122) vs 16.5%(20/121)
Anorexia: 5.6%(7/126) vs 8.5%(10/118) vs 4.9%(6/122) vs 10.7%(13/121)
Asthenia: 9.5%(12/126) vs 5.9%(7/118) vs 9.0%(11/122) vs 2.5%(3/121)
Back Pain: 6.3%(8/126) vs 5.1%(6/118) vs 3.3%(4/122) vs 3.3%(4/121)
Confusion: 4.8%(6/126) vs 2.5%(3/118) vs 7.4%(9/122) vs 4.1%(5/121)
Conjunctivitis: 2.4%(3/126) vs 5.9%(7/118) vs 2.5%(3/122) vs 2.5%(3/121)
Constipation: 3.2%(4/126) vs 5.1%(6/118) vs 4.9%(6/122) vs 5.0%(6/121)
Coughing: 5.6%(7/126) vs 5.1%(6/118) vs 3.3%(4/122) vs 5.0%(6/121)
Diarrhea: 8.7%(11/126) vs 5.9%(7/118) vs 6.6%(8/122) vs 5.8%(7/121)
EPS: 7.1%(9/126) vs 7.6%(9/118) vs 7.4%(9/122) vs 5.8%(7/121)
Ecchymosis: 8.7%(11/126) vs 8.5%(10/118) vs 4.9%(6/122) vs 9.9%(12/121)
Edema: 1.6%(2/126) vs 5.1%(6/118) vs 3.3%(4/122) vs 1.7%(2/121)
Edema, Peripheral: 8.7%(11/126) vs 10.2%(12/118) vs 5.7%(7/122) vs 8.3%(10/121)
Extremity Pain: 9.5%(12/126) vs 6.8%(8/118) vs 9.0%(11/122) vs 5.8%(7/121)
Headache: 7.1%(9/126) vs 4.2%(5/118) vs 4.1%(5/122) vs 3.3%(4/121)
Incidence Of Clinically Significant Weight Gain: 4.0%(5/126) vs 6.8%(8/118) vs 4.1%(5/122) vs 5.8%(7/121)
Incidence Of Clinically Significant Weight Loss: 11.1%(14/126) vs 10.2%(12/118) vs 13.1%(16/122) vs 14.9%(18/121)
Increased Salivation: 1.6%(2/126) vs 1.7%(2/118) vs 7.4%(9/122) vs 0.8%(1/121)
Insomnia: 4.8%(6/126) vs 9.3%(11/118) vs 5.7%(7/122) vs 8.3%(10/121)
Lightheadedness: 3.2%(4/126) vs 5.1%(6/118) vs 4.1%(5/122) vs 0.0%(0/121)
Rash: 7.9%(10/126) vs 9.3%(11/118) vs 9.0%(11/122) vs 8.3%(10/121)
Skin Ulcer: 8.7%(11/126) vs 10.2%(12/118) vs 11.5%(14/122) vs 7.4%(9/121)
Mintzer et al. 2007107

Continued
Somnolence: 7.1%(9/126) vs 3.4%(4/118) vs 9.8%(12/122) vs 3.3%(4/121)
Upper Respiratory Infection: 4.8%(6/126) vs 8.5%(10/118) vs 4.9%(6/122) vs 5.0%(6/121)
Urinary Incontinence: 5.6%(7/126) vs 1.7%(2/118) vs 9.8%(12/122) vs 1.7%(2/121)
Urinary-Tract Infection: 19.8%(25/126) vs 16.1%(19/118) vs 18.9%(23/122) vs 13.2%(16/121)
Vomiting: 6.3%(8/126) vs 11.0%(13/118) vs 9.0%(11/122) vs 6.6%(8/121)
Weight Loss: 4.0%(5/126) vs 5.1%(6/118) vs 4.9%(6/122) vs 3.3%(4/121)

Withdrawals:
Aripiprazole 10 mg vs Aripiprazole 2 mg vs Aripiprazole 5 mg vs Placebo
Withdrawals:45.2%(57/126) vs 34.7%(41/118) vs 40.2%(49/122) vs 46.3%(56/121)
Withdrawals Due To Adverse Events:24.6%(31/126) vs 7.6%(9/118) vs 18.0%(22/122) vs 13.2%(16/121)
Naber et al. 2007128

Dementia/Agitation

Risperidone

Location: Not reported

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Community practice

Jadad: 3

Age: Mean: 49

Sex: Mixed

Race: Not reported

Screened: NR
Eligible: NR
Entering: 815
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Not reported
Inclusion criteria:
>=55, ICD-10 diagnosis of unspecified organic personality and behavioral disorder due to brain disease, damage and dysfunction, specific symptoms on PANSS

Exclusion criteria:
Not reported

Interventions:
Placebo for 12 weeks
 vs
Risperidone 0.5-4 mg/days flexible dose for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56, 84 days
Results:
Dementia: No data

Adverse Events:
Placebo vs Risperidone
Aes “related To Study Medication”: 23.6%(48/203) vs 24.8%(152/612)
Aes That Occurred In >5% Of Each Group: 0.0%(0/203) vs 0.0%(0/612)
All Cardiovascular Adverse Events (Cae): 1.0%(2/203) vs 0.7%(4/612)
Cardiovascular Adverse Event: Hospitalized After 74 D Treatment Due To Transient Speech Disorder And Disorientation; Diagnosed With Transient Ischemic Attack (Article Says “doubtful” It Was Related To Tx): 0.5%(1/203) vs 0.0%(0/612)
Cardiovascular Adverse Event: Left Ventricular Failure And Acute Dextrocerebral Insult After 33 D Treatment; Died 2 D Later (Article Says Unrelated To Tx): 0.5%(1/203) vs 0.0%(0/612)
Cardiovascular Adverse Event: Mild Unrest, Anxiety, Fear Of Drugs At End Of Week 3 Of Treatment; Could Not Speak For 1 D After 43 D Of Treatment; Suspected Transient Ischemic Attack; Medication Continued And Patient Completed Study (Article Says Unrelated To Tx): 0.0%(0/203) vs 0.2%(1/612)
Cardiovascular Adverse Event: Mild Vertigo After 27 D Treatment, Diagnosed As Cerebral Circulatory Disorder With Suspicion Of Prolonged Reversible Ischemic Neurologic Deficit; Event Resolved After 6 D And Patient Continued Study (Article Says “possibly” Related To Tx): 0.0%(0/203) vs 0.2%(1/612)
Cardiovascular Adverse Event: Paraesthesia In Extremities After 13 D Treatment, Transient Ischemic Attack Suspected And Patient, Hospitalized; Event Resolved After 36 D (Articles Says Unrelated To Tx): 0.0%(0/203) vs 0.2%(1/612)
Cardiovascular Adverse Event: Transient Ischemic Attack After 89 D Treatment; Hospitalized For 6 D (Article Says Unrelated To Tx): 0.0%(0/203) vs 0.2%(1/612)
Death During The Study Or Within 32 Days Of Study End (Article Says Unrelated To Study Medication): 2.5%(5/203) vs 0.8%(5/612)
Eps Occurrence: 0.5%(1/203) vs 2.0%(12/612)
Frequency Of Adverse Events: 31.5%(64/203) vs 35.0%(214/612)

Withdrawals:
Placebo vs Risperidone
Withdrawals:10.3%(21/203) vs 9.8%(60/612)
Withdrawals Due To Adverse Events:6.4%(13/203) vs 6.5%(40/612)
Zhong et al. 2007122

Dementia/Agitation

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center, Long-term care facilities

Jadad: 5

Age: Mean: 56

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic, Asian/Pacific Islander, Other-NOS

Screened: 435
Eligible: NR
Entering: 333
Withdrawn: 118
Lost to follow-up: NR
Analyzed: 215

Method of AE assessment: Monitored
Inclusion criteria:
Institutionalized, diagnosed possible AD or vascular dementia, age >= 55, ambulatory, agitation that didn't result directly from participants medical condition, PANSS-EC total >= 14, one of the 5 PANSS-EC items >= 4.

Exclusion criteria:
History of schizophrenia, schizoaffective or bipolar disorder, agitation not related to dementia, failure to respond to a prior adequate AAP trial for agitation, unstable medical illness, abnormal ECG results.

Interventions:
Placebo for 10 weeks
 vs
Quetiapine 25-100 mg/days fixed titration schedule for 10 weeks
 vs
Quetiapine 25-200 mg/days fixed titration schedule for 10 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 28, 42, 56, 70 days
Results:
Dementia: Change in NPI agitation (Agitation) at 10 weeks:
Placebo vs Quetiapine (all doses combined) - SMD = -0.03 ( -0.27 , 0.21 )

Dementia: Change in NPI psy (Psychosis) at 10 weeks:
Placebo vs Quetiapine (all doses combined) - SMD = -0.03 ( -0.27 , 0.21 )

Dementia: Change in NPI total (Total) at 10 weeks:
Placebo vs Quetiapine (all doses combined) - SMD = 0.04 ( -0.21 , 0.28 )

Adverse Events:
Placebo vs Quetiapine 100 mg vs Quetiapine 200 mg
Any Adverse Events: 80.4%(74/92) vs 80.6%(100/124) vs 84.6%(99/117)
Cardiovascular: 4.3%(4/92) vs 1.6%(2/124) vs 5.1%(6/117)
Constipation: 1.1%(1/92) vs 5.6%(7/124) vs 6.0%(7/117)
Decreased Appetite: 3.3%(3/92) vs 1.6%(2/124) vs 6.0%(7/117)
EPS: 5.4%(5/92) vs 4.8%(6/124) vs 6.8%(8/117)
Fall: 26.1%(24/92) vs 25.8%(32/124) vs 26.5%(31/117)
Gait Abnormalities: 0.0%(0/92) vs 4.8%(6/124) vs 5.1%(6/117)
Headache: 3.3%(3/92) vs 5.6%(7/124) vs 3.4%(4/117)
Lethargy: 3.3%(3/92) vs 6.5%(8/124) vs 11.1%(13/117)
Nausea: 2.2%(2/92) vs 5.6%(7/124) vs 4.3%(5/117)
Peripheral Edema: 6.5%(6/92) vs 7.3%(9/124) vs 5.1%(6/117)
Sedation: 3.3%(3/92) vs 3.2%(4/124) vs 7.7%(9/117)
Serious Adverse Events: 9.8%(9/92) vs 11.3%(14/124) vs 6.8%(8/117)
Skin Laceration: 14.1%(13/92) vs 15.3%(19/124) vs 11.1%(13/117)
Somnolence: 2.2%(2/92) vs 8.1%(10/124) vs 9.4%(11/117)
Upper Respiratory Tract Infection: 4.3%(4/92) vs 4.8%(6/124) vs 5.1%(6/117)
Urinary Tract Infection: 7.6%(7/92) vs 16.1%(20/124) vs 7.7%(9/117)
Vomiting: 3.3%(3/92) vs 5.6%(7/124) vs 9.4%(11/117)
Weight Decreased: 5.4%(5/92) vs 4.0%(5/124) vs 3.4%(4/117)

Withdrawals:
Placebo vs Quetiapine 100 mg vs Quetiapine 200 mg
Withdrawals:34.8%(32/92) vs 34.7%(43/124) vs 36.8%(43/117)
Withdrawals Due To Adverse Events:9.8%(9/92) vs 8.1%(10/124) vs 14.5%(17/117)
Streim et al. 2008108

Dementia/Agitation

Aripiprazole

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center, Long-term care facilities

Jadad: 3

Age: Mean: 59

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic, Asian/Pacific Islander

Screened: 330
Eligible: 256
Entering: 256
Withdrawn: 105
Lost to follow-up: 0
Analyzed: 151

Method of AE assessment: Monitored
Inclusion criteria:
Age 55-95 with AD, had psychotic symptoms for greater than/equal to 1month, institutionalized for more than 4 weeks, have a MMSE score 6-22 and NPI-NH>=6

Exclusion criteria:
Delirium or schizophrenia, mood disorder, continuous symptoms of psychosis before dementia, psychotic symptoms better accounted for any drug, depression with symptoms of psychosis, non-AD-type dementia, seizure, unstable thyroid pathology, suicide intention, potential to subject to AE, had participated in clinical study

Interventions:
Placebo for 10 weeks
 vs
Aripiprazole 0.7-15 mg/days flexible dose for 10 weeks

Run-in/wash-out period:
Wash-out: No drug for 7 day(s).

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 42, 56, 70 days
Results:
Dementia: Change in CMAI (Agitation) at 10 weeks:
Placebo vs Aripriprazole flexible dose - SMD = 0.30 ( 0.05 , 0.55 )

Dementia: Change in NPI psy (Psychosis) at 10 weeks:
Placebo vs Aripriprazole flexible dose - SMD = -0.02 ( -0.27 , 0.23 )

Dementia: Change in NPI total (Total) at 10 weeks:
Placebo vs Aripriprazole flexible dose - SMD = 0.36 ( 0.11 , 0.61 )

Adverse Events:
Aripiprazole vs Placebo
Accidental Injury: 20.6%(27/131) vs 28.8%(36/125)
Agitation: 7.6%(10/131) vs 12.0%(15/125)
Asthenia: 12.2%(16/131) vs 6.4%(8/125)
Cerebrovascular Accident: 0.0%(0/131) vs 0.8%(1/125)
EPS-Related Adverse Events: 5.3%(7/131) vs 4.0%(5/125)
Ecchymosis: 12.2%(16/131) vs 12.8%(16/125)
Orthostatic Events (Hypotension Or Syncope): 3.1%(4/131) vs 4.8%(6/125)
Potentially Clinically Significant Increases In QTc Interval: 1.5%(2/131) vs 0.8%(1/125)
Potentially Significant Low Hemoglobin Levels: 10.7%(14/131) vs 6.4%(8/125)
Rash: 9.9%(13/131) vs 12.0%(15/125)
Serious Adverse Events Of Accidental Injury: 1.5%(2/131) vs 4.8%(6/125)
Somnolence: 13.7%(18/131) vs 4.0%(5/125)
Total Serious Adverse Events: 12.2%(16/131) vs 13.6%(17/125)
Ulcer Skin: 9.2%(12/131) vs 12.0%(15/125)
Urinary Tract Infection: 13.7%(18/131) vs 10.4%(13/125)
Vomiting: 9.9%(13/131) vs 8.0%(10/125)

Withdrawals:
Aripiprazole vs Placebo
Death During The Study Or Within 30 Days Of Withdrawal:2.3%(3/131) vs 2.4%(3/125)
Withdrawals:33.6%(44/131) vs 48.8%(61/125)
Withdrawals Due To Abnormal Lab Test Results:0.0%(0/131) vs 0.0%(0/125)
Withdrawals Due To Adverse Events:13.0%(17/131) vs 8.0%(10/125)
Withdrawals Due To ECG Abnormality Including Prolongation Of The QTc Interval:0.0%(0/131) vs 0.0%(0/125)
Withdrawals Due To Weight Loss:0.0%(0/131) vs 0.0%(0/125)
Rappaport et al. 2009109

Dementia/Agitation

Aripiprazole

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Mean: 80

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic, Other-NOS

Screened: 150
Eligible: 129
Entering: 116
Withdrawn: 2
Lost to follow-up: 0
Analyzed: 115

Method of AE assessment: Monitored
Inclusion criteria:
Diagnosed with AD, vascular, or mixed dementia, in healthcare facilities, moderate to severe acute exacerbation of agitated behaviors, able to comply with protocol

Exclusion criteria:
Other major psychiatric disorders, history of neuroleptic malignant syndrome, seizure, stroke, severe head trauma

Interventions:
Placebo for 24 hours
 vs
Aripiprazole 5 mg/Not reported average final dose for 24 hours
 vs
Aripiprazole 10 mg/Not reported average final dose for 24 hours

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 2, 4, 6, 12, 24 hours
Results:
Dementia: Change in ACES (Agitation) at 0.14 weeks:
Placebo vs Aripriprazole (all doses combined) - SMD = 5.00 ( 4.24 , 5.76 )

Adverse Events:
Aripiprazole 10 mg vs Aripiprazole 15 mg vs Aripiprazole 5 mg vs Placebo
Agitation: 1.3%(1/78) vs 0.0%(0/13) vs 0.0%(0/12) vs 7.7%(2/26)
Any Adverse Event: 52.6%(41/78) vs 69.2%(9/13) vs 50.0%(6/12) vs 30.8%(8/26)
Cerebrovascular AE (Acute Stroke) 16 Days After Treatment (Judged Unlikely To Be Treatment-Related): 1.3%(1/78) vs 0.0%(0/13) vs 0.0%(0/12) vs 0.0%(0/26)
Clinically Significant Vital Signs Or Electrocardiograms: 0.0%(0/78) vs 0.0%(0/13) vs 0.0%(0/12) vs 0.0%(0/26)
Death 24 Days After Treatment (Not Reasonably Linked To Study Medication): 1.3%(1/78) vs 0.0%(0/13) vs 0.0%(0/12) vs 0.0%(0/26)
Dementia: 0.0%(0/78) vs 0.0%(0/13) vs 25.0%(3/12) vs 0.0%(0/26)
EPS: 0.0%(0/78) vs 0.0%(0/13) vs 0.0%(0/12) vs 0.0%(0/26)
Electrocardiogram Change: 0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Fall: 0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 3.8%(1/26)
Femoral Neck Fracture: 0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Insomnia: 2.6%(2/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Irregular Heart Rate: 0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Lethargy: 0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Pyrexia: 0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Serious AE: 7.7%(6/78) vs 7.7%(1/13) vs 25.0%(3/12) vs 7.7%(2/26)
Skin Laceration: 1.3%(1/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 7.7%(2/26)
Somnolence: 38.5%(30/78) vs 38.5%(5/13) vs 16.7%(2/12) vs 7.7%(2/26)
Vomiting: 3.8%(3/78) vs 0.0%(0/13) vs 8.3%(1/12) vs 0.0%(0/26)

Withdrawals:
Aripiprazole 10 mg vs Aripiprazole 15 mg vs Aripiprazole 5 mg vs Placebo
Femoral Neck Fracture Resulting From A Fall On Wet Floor And Leading To Withdrawal:0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Withdrawals:0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 3.8%(1/26)
Withdrawals Due To Adverse Events:0.0%(0/78) vs 7.7%(1/13) vs 0.0%(0/12) vs 0.0%(0/26)
Paleacu et al. 2008123

Dementia/Agitation

Quetiapine

Location: Israel

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Not reported

Sex: Mixed

Race: Not reported

Screened: 44
Eligible: 40
Entering: 40
Withdrawn: 12
Lost to follow-up: 1
Analyzed: 27

Method of AE assessment: Monitored, reported spontaneously by patient
Inclusion criteria:
AD with BPSD, age > 50, MMSE < 24, NPI > 6 on any item

Exclusion criteria:
Other types of dementia, malignancy, heart disease, women of child-bearing potential, alcohol or drug abuse

Interventions:
Placebo for 6 weeks
 vs
Quetiapine 50-300 mg/days flexible dose for 6 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42 days
Results:
Dementia: Change in NPI agitation (Agitation) at 6 weeks:
Placebo vs Quetiapine - SMD = -0.48 ( -1.11 , 0.15 )

Adverse Events:
Quetiapine vs Placebo
Akathisia: 0.0%(0/20) vs 5.0%(1/20)
Confusion Urinary Tract Infection: 5.0%(1/20) vs 0.0%(0/20)
Diarrhea: 0.0%(0/20) vs 5.0%(1/20)
Dizziness: 0.0%(0/20) vs 5.0%(1/20)
Dry Mouth: 5.0%(1/20) vs 0.0%(0/20)
Edema: 0.0%(0/20) vs 5.0%(1/20)
Elevated Systolic Bp (190/90): 5.0%(1/20) vs 0.0%(0/20)
Falls: 0.0%(0/20) vs 10.0%(2/20)
Headaches: 5.0%(1/20) vs 0.0%(0/20)
Parkinsonism: 5.0%(1/20) vs 5.0%(1/20)
Sedation: 5.0%(1/20) vs 0.0%(0/20)
Tremor: 0.0%(0/20) vs 5.0%(1/20)

Withdrawals:
Quetiapine vs Placebo
Withdrawals:40.0%(8/20) vs 25.0%(5/20)
Withdrawals Due To Adverse Events:5.0%(1/20) vs 5.0%(1/20)
Mintzer et al. 2006129

Dementia/Agitation

Risperidone

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center, Long-term care facilities

Jadad: 3

Age: Mean: 83

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic, Asian/Pacific Islander, Other-NOS

Screened: 560
Eligible: 473
Entering: 473
Withdrawn: 117
Lost to follow-up: 1
Analyzed: 354

Method of AE assessment: Monitored
Inclusion criteria:
>= 55 years old, residents of nursing homes or long-term care facilities, mobile, met the criteria for psychosis of AD, in need of treatment with an atypical antipsychotic, scored >=2 on any item of the BEHAVE-AD psychosis subscale, MMSE 5-23

Exclusion criteria:
Recently treated with neuroleptic injections, had other medical conditions that diminish cognition, had other psychiatric disorders that produce psychotic symptoms, patients with epilepsy, cancer, unstable medical conditions

Interventions:
Placebo for 8 weeks
 vs
Risperidone 0.5-2.5 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Run-in: Placebo for 1-16 day(s). Patients still eligible after washout were randomized.

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 42, 56 days
Results:
Dementia: Change in BEHAVE-AD agg (Agitation) at 8 weeks:
Placebo vs Risperidone - SMD = 0.04 ( -0.16 , 0.23 )

Dementia: Change in BEHAVE-AD psy (Psychosis) at 8 weeks:
Placebo vs Risperidone - SMD = 0.17 ( -0.02 , 0.36 )

Dementia: Change in BEHAVE-AD total (Total) at 8 weeks:
Placebo vs Risperidone - SMD = -0.01 ( -0.21 , 0.18 )

Adverse Events:
Placebo vs Risperidone
Agitation: 6.7%(16/238) vs 8.1%(19/235)
Any Adverse Event: 63.9%(152/238) vs 74.5%(175/235)
Death: 0.0%(0/238) vs 0.9%(2/235)
Edema-Related: 4.6%(11/238) vs 5.1%(12/235)
Extrapyramidal Symptoms-Related: 3.4%(8/238) vs 8.5%(20/235)
Fall: 12.6%(30/238) vs 11.1%(26/235)
Glucose-Related: 2.1%(5/238) vs 1.7%(4/235)
Hematoma: 5.0%(12/238) vs 3.4%(8/235)
Injury: 10.5%(25/238) vs 9.4%(22/235)
Insomnia: 5.9%(14/238) vs 5.5%(13/235)
Potentially Prolactin-Related: 0.0%(0/238) vs 0.0%(0/235)
Serious Adverse Event: 13.0%(31/238) vs 14.0%(33/235)
Somnolence: 4.6%(11/238) vs 16.2%(38/235)
Stroke: 0.4%(1/238) vs 0.4%(1/235)
Tardive Dyskinesia: 0.0%(0/238) vs 0.0%(0/235)
Transient Ischemic Attack: 0.0%(0/238) vs 1.3%(3/235)
Urinary Tract Infection: 10.1%(24/238) vs 9.4%(22/235)

Withdrawals:
Placebo vs Risperidone
Withdrawals:24.8%(59/238) vs 25.1%(59/235)
Withdrawals Due To Adverse Events:10.1%(24/238) vs 10.6%(25/235)
Cutler et al. 2009171

Depression

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 5

Age: Mean: 18

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: 912
Eligible: NR
Entering: 612
Withdrawn: 138
Lost to follow-up: 32
Analyzed: 370

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
18-65 years old, diagnosed MDD, HAM-D total score >=22, HAM-D item 1 score >=>= at enrollment and randomization

Exclusion criteria:
DSM-IV AXIS I/II disorders duration of current MDD >= 12 months or <=4 weeks, inadequate response to at least 6 weeks of treatment with 2 or more classes of antidepressants during current episode, clinically significant medical illness, psychotic feature

Interventions:
Placebo for 6 weeks
 vs
Quetiapine 50-150 mg/days fixed titration schedule for 6 weeks
 vs
Quetiapine 50-300 mg/days fixed titration schedule for 6 weeks
 vs
Haldol 60 mg/days fixed single dose for 6 weeks

Run-in/wash-out period:
Wash-out: No drug for 7-28 day(s). Eligible patents were randomized.

Comorbidities:
None

Timing of outcome assessment: 7, 14, 28, 42, 56 days
Results:
Depression: Change in MADRS (% Remitted) at 6 weeks:
Quetiapine vs Placebo - RR = 1.43 ( 1.03 , 2.06 )

Depression: Change in MADRS (% Responder) at 6 weeks:
Quetiapine vs Placebo - RR = 1.51 ( 1.20 , 1.91 )

Adverse Events:
Duloxetine 60 mg/d vs Placebo vs Quetiapine 150 mg/d vs Quetiapine 300 mg/d >= 7% Increase In Body Weight: 0.7%(1/151) vs 0.0%(0/157) vs 2.0%(3/152) vs 3.3%(5/152)
Abnormal Dreams: 2.6%(4/151) vs 0.6%(1/157) vs 6.6%(10/152) vs 2.0%(3/152)
Clinically Important Elevated Glucose (=126 mg/dL) at endpoint: 0.7%(1/151) vs 0.6%(1/157) vs 2.0%(3/152) vs 3.9%(6/152)
Constipation: 11.3%(17/151) vs 6.4%(10/157) vs 5.9%(9/152) vs 8.6%(13/152)
Decreased Appetite: 5.3%(8/151) vs 0.6%(1/157) vs 3.3%(5/152) vs 0.0%(0/152)
Diarrhea: 10.6%(16/151) vs 6.4%(10/157) vs 4.6%(7/152) vs 2.6%(4/152)
Dizziness: 16.6%(25/151) vs 10.8%(17/157) vs 14.5%(22/152) vs 19.1%(29/152)
Dry Mouth: 18.5%(28/151) vs 8.9%(14/157) vs 33.6%(51/152) vs 38.2%(58/152)
Dyspepsia: 5.3%(8/151) vs 3.2%(5/157) vs 3.9%(6/152) vs 5.3%(8/152)
Fatigue: 6.6%(10/151) vs 0.0%(0/157) vs 2.6%(4/152) vs 5.3%(8/152)
Headache: 17.9%(27/151) vs 10.2%(16/157) vs 10.5%(16/152) vs 9.2%(14/152)
Hyperhidrosis: 7.3%(11/151) vs 0.6%(1/157) vs 0.0%(0/152) vs 0.0%(0/152)
Increased Appetite: 2.0%(3/151) vs 1.9%(3/157) vs 5.9%(9/152) vs 3.9%(6/152)
Insomnia: 14.6%(22/151) vs 7.0%(11/157) vs 1.3%(2/152) vs 1.3%(2/152)
Irritability: 0.0%(0/151) vs 4.5%(7/157) vs 1.3%(2/152) vs 5.9%(9/152)
Nausea: 35.8%(54/151) vs 9.6%(15/157) vs 10.5%(16/152) vs 5.3%(8/152)
Pollakiuria: 5.3%(8/151) vs 1.3%(2/157) vs 3.3%(5/152) vs 2.0%(3/152)
Sedation: 15.9%(24/151) vs 5.1%(8/157) vs 38.8%(59/152) vs 36.8%(56/152)
Somnolence: 12.6%(19/151) vs 7.0%(11/157) vs 24.3%(37/152) vs 27.0%(41/152)
Upper Respiratory Tract Infection: 4.0%(6/151) vs 7.0%(11/157) vs 2.0%(3/152) vs 2.6%(4/152)
Vision Blurred: 2.6%(4/151) vs 1.9%(3/157) vs 5.3%(8/152) vs 5.3%(8/152)

Withdrawals:
Duloxetine 60 mg/d vs Placebo vs Quetiapine 150 mg/d vs Quetiapine 300 mg/d
Withdrawals:30.5%(46/151) vs 21.0%(33/157) vs 34.2%(52/152) vs 25.7%(39/152)
Withdrawals Due To Adverse Events:13.2%(20/151) vs 4.5%(7/157) vs 19.7%(30/152) vs 15.1%(23/152)
Withdrawals Due To Of Death:0.0%(0/151) vs 0.0%(0/157) vs 0.7%(1/152) vs 0.0%(0/152)
Weisler et al. 2009172

Depression

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 5

Age: Mean: 18

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: 1075
Eligible: 723
Entering: 723
Withdrawn: 127
Lost to follow-up: 85
Analyzed: 511

Method of AE assessment: Monitored
Inclusion criteria:
18-65, output, MDD, HAM-D item 17>=22, HAM-D item 1>=2

Exclusion criteria:
Other axis I disorders during prior 6 month, Axis II impacting status, current MDD episode > 12 months or <4 weeks, inadequate response to adequate antidepressants treatment with >= 2 classes of antidepressants, medical illness, suicide or homicide risk

Interventions:
Placebo for 6 weeks
 vs
Quetiapine 50 mg/days fixed titration schedule for 6 weeks
 vs
Quetiapine 50-150 mg/days fixed titration schedule for 6 weeks
 vs
Quetiapine 50-300 mg/days fixed titration schedule for 6 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 4, 7, 14, 28, 42 days
Results:
Depression: Change in MADRS (% Remitted) at 6 weeks:
Quetiapine vs Placebo - RR = 1.27 ( 0.89 , 1.82 )

Depression: Change in MADRS (% Responder) at 6 weeks:
Quetiapine vs Placebo - RR = 1.58 ( 1.24 , 2.02 )

Adverse Events:
Placebo vs Quetiapine 150mg vs Quetiapine 300mg vs Quetiapine 50mg
Any Adverse Event: 67.9%(125/184) vs 87.1%(155/178) vs 87.7%(157/179) vs 80.2%(146/182)
Back Pain: 2.2%(4/184) vs 5.6%(10/178) vs 5.0%(9/179) vs 1.6%(3/182)
Constipation: 2.7%(5/184) vs 8.4%(15/178) vs 8.9%(16/179) vs 7.1%(13/182)
Death: 0.0%(0/184) vs 0.0%(0/178) vs 0.0%(0/179) vs 0.0%(0/182)
Diarrhea: 8.7%(16/184) vs 6.2%(11/178) vs 3.4%(6/179) vs 6.6%(12/182)
Dizziness: 5.4%(10/184) vs 10.7%(19/178) vs 10.6%(19/179) vs 8.8%(16/182)
Dry Mouth: 8.7%(16/184) vs 37.1%(66/178) vs 41.3%(74/179) vs 22.0%(40/182)
Dyspepsia: 2.7%(5/184) vs 5.6%(10/178) vs 2.8%(5/179) vs 2.2%(4/182)
Fatigue: 4.3%(8/184) vs 7.9%(14/178) vs 6.1%(11/179) vs 6.0%(11/182)
Headache: 14.7%(27/184) vs 13.5%(24/178) vs 14.5%(26/179) vs 12.1%(22/182)
Increased Appetite: 3.8%(7/184) vs 5.1%(9/178) vs 4.5%(8/179) vs 4.4%(8/182)
Insomnia: 7.6%(14/184) vs 6.7%(12/178) vs 6.7%(12/179) vs 4.9%(9/182)
Irritability: 3.8%(7/184) vs 5.6%(10/178) vs 3.4%(6/179) vs 6.0%(11/182)
Myalgia: 1.6%(3/184) vs 7.3%(13/178) vs 2.2%(4/179) vs 4.4%(8/182)
Nausea: 6.0%(11/184) vs 8.4%(15/178) vs 8.9%(16/179) vs 7.7%(14/182)
Sedation: 6.0%(11/184) vs 35.4%(63/178) vs 30.7%(55/179) vs 26.9%(49/182)
Somnolence: 10.9%(20/184) vs 19.7%(35/178) vs 29.1%(52/179) vs 18.1%(33/182)
Vomiting: 2.2%(4/184) vs 2.2%(4/178) vs 6.7%(12/179) vs 1.6%(3/182)

Withdrawals:
Placebo vs Quetiapine 150mg vs Quetiapine 300mg vs Quetiapine 50mg
Withdrawals:27.2%(50/184) vs 30.9%(55/178) vs 33.0%(59/179) vs 26.4%(48/182)
Withdrawals Due To Adverse Events:6.0%(11/184) vs 14.0%(25/178) vs 19.0%(34/179) vs 8.2%(15/182)
Chaput et al. 2008158

Depression

Quetiapine

Location: Canada

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 2

Age: Mean: 23

Sex: Mixed

Race: Not reported

Screened: 40
Eligible: 24
Entering: 22
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 15

Method of AE assessment: Monitored
Inclusion criteria:
MD, HRSD >= 20, CGI-S >=4, 2 classes of antidepressants

Exclusion criteria:
Suicide risk, pregnant, breast feeding, not on birth control for 3 month prior, bipolar, schizophrenia, personality disorder, panic, anxiety, OCD, somatoformor organic mental disorder, anorexia, bulimia, substance abuse, other psychotropics, unstable medical illness

Interventions:
Placebo 12.5-200 mg/days flexible dose for 12 weeks
 vs
Quetiapine 12.5-200 mg/days flexible dose for 12 weeks

Run-in/wash-out period:
Run-in: Lithium for 3 week(s). Non-responders were randomized.
In Wash-out: No drug for 8 day(s). Patients still eligible after washout were randomized.

Comorbidities:
None

Timing of outcome assessment: 21, 28, 42, 56, 70, 84, 98 days
Results:
Depression: Only data on placebo group reported

Adverse Events:
Quetiapine/CBT vs. Placebo/CBT
Dry Mouth: 36.4%(4/11) vs 9.1%(1/11)
Gastrointestinal Discomfort: 18.2%(2/11) vs 27.3%(3/11)
Headache: 36.4%(4/11) vs 9.1%(1/11)
Insomnia: 45.5%(5/11) vs 18.2%(2/11)
Labile Hypertension: 9.1%(1/11) vs 9.1%(1/11)
Mild Akathisia And Muscle Rigidity: 0.0%(0/11) vs 9.1%(1/11)
Nausea: 18.2%(2/11) vs 18.2%(2/11)
Somnolence: 63.6%(7/11) vs 9.1%(1/11)

Withdrawals:
Quetiapine/CBT vs Placebo/CBT
Possible Anomaly Detected At The Week 10 Electrocardiogram That Was Ultimately Found To Be A False Positive Result Leading To Withdrawal:9.1%(1/11) vs 0.0%(0/11)
Withdrawals:9.1%(1/11) vs 54.5%(6/11)
Withdrawals Due To Adverse Events:0.0%(0/11) vs 0.0%(0/11)
AstraZeneca 2008173

Depression

Quetiapine

Location: US, Canada, Western Europe, South Africa

Trial: AMETHYST

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Mean: 19

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: NR
Eligible: NR
Entering: 776
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
Age 18-65, with DSM-IV diagnosis of MDD together with an acute depressed episode confirmed by MINI, have a current episode of depression >=4 weeks and <12 months in duration, HAM-D total score >=20, HAM-D item 1 score >=2, MADRS score <=12, CGI-S score <=3

Exclusion criteria:
Not reported

Interventions:
Placebo 50-300 mg/days flexible dose for 52 weeks
 vs
Quetiapine 50-300 mg/days flexible dose for 52 weeks

Run-in/wash-out period:
Run-in: Antipsychotics for 26 week(s).
Patients who met the study criteria were randomized.

Comorbidities:
None

Timing of outcome assessment: 364 days
Results:
Depression: Change in MADRS (Total) at 52 weeks:
Quetiapine vs Placebo - WMD = -1.88 ( -1.91 , -1.85 )

Adverse Events:
Placebo
Serious AE Leading To Death (Hypertension): 0.3%(1/385)
Placebo vs Quetiapine
“drug-Related Ae”: 28.3%(109/385) vs 33.0%(129/391)
>=15 bpm Increases In Heart Rate: 6.5%(25/385) vs 10.2%(40/391)
>=7% Increase In Weight: 2.9%(11/385) vs 5.4%(21/391)
AE Potentially Related To Neutropenia Or Agranulocytosis: 0.0%(0/385) vs 0.0%(0/391)
AE Potentially Related To Qt Prolongation: 0.0%(0/385) vs 0.0%(0/391)
AEs Potentially Related To Nausea And Vomiting: 10.9%(42/385) vs 4.9%(19/391)
Anxiety: 2.6%(10/385) vs 1.3%(5/391)
Any AE: 60.5%(233/385) vs 62.9%(246/391)
Arthralgia: 2.3%(9/385) vs 4.9%(19/391)
Back Pain: 2.6%(10/385) vs 3.8%(15/391)
Blood Pressure Increased: 0.5%(2/385) vs 2.3%(9/391)
Constipation: 0.3%(1/385) vs 2.0%(8/391)
Decreases =20 Millimeters Of Mercury In Orthostatic Systolic Blood Pressure: 6.2%(24/385) vs 11.5%(45/391)
Diarrhea: 6.8%(26/385) vs 5.4%(21/391)
Disturbance In Attention: 0.0%(0/385) vs 0.0%(0/391)
Dizziness: 4.4%(17/385) vs 6.6%(26/391)
Dry Mouth: 1.6%(6/385) vs 3.6%(14/391)
Dyspepsia: 0.0%(0/385) vs 0.0%(0/391)
Edema Peripheral: 0.0%(0/385) vs 0.0%(0/391)
Fatigue: 2.6%(10/385) vs 4.3%(17/391)
Headache: 11.4%(44/385) vs 6.9%(27/391)
Incidence Of Syncope: 0.0%(0/385) vs 0.8%(3/391)
Increased Appetite: 0.0%(0/385) vs 0.0%(0/391)
Increases =15 Bpm In Supine Pulse: 19.2%(74/385) vs 28.1%(110/391)
Insomnia: 14.8%(57/385) vs 5.6%(22/391)
Irritability: 3.1%(12/385) vs 0.8%(3/391)
Lethargy: 0.0%(0/385) vs 0.0%(0/391)
Musculoskeletal Pain: 1.3%(5/385) vs 2.0%(8/391)
Myalgia: 1.3%(5/385) vs 2.3%(9/391)
Nasopharyngitis: 6.5%(25/385) vs 7.2%(28/391)
Nausea: 9.9%(38/385) vs 3.6%(14/391)
Pain In Extremity: 2.1%(8/385) vs 1.5%(6/391)
QTcF Values >=450ms: 2.6%(10/385) vs 2.6%(10/391)
Restlessness: 0.0%(0/385) vs 0.0%(0/391)
Sedation: 0.3%(1/385) vs 2.6%(10/391)
Serious Ae, All: 2.1%(8/385) vs 2.0%(8/391)
Sinusitis: 2.3%(9/385) vs 3.1%(12/391)
Somnolence: 0.0%(0/385) vs 3.8%(15/391)
Tx Emergent Shift From <3 To =3 Metabolic Risk Factors: 12.7%(49/385) vs 17.6%(69/391)
Upper Respiratory Tract Infection: 4.2%(16/385) vs 3.8%(15/391)
Urinary Tract Infection: 1.0%(4/385) vs 2.3%(9/391)
Vision Blurred: 0.0%(0/385) vs 0.0%(0/391)
Vomiting: 2.3%(9/385) vs 2.0%(8/391)
Weight Increased: 1.6%(6/385) vs 9.7%(38/391)
Quetiapine
Serious Ae Leading To Death: 0.0%(0/391)

Withdrawals:
Placebo vs Quetiapine
Withdrawals Due To Adverse Events:5.2%(20/385) vs 6.4%(25/391)
AstraZeneca 2008169

Depression

Quetiapine

Location: US, Eastern Europe, Latin America

Trial: SAPPHIRE

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Mean: 66

Sex: Mixed

Race: Caucasian, African Ancestry, Other-NOS

Screened: NR
Eligible: NR
Entering: 338
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 224

Method of AE assessment: Monitored
Inclusion criteria:
Age >=66, DSM-IV diagnosis of MDD confirmed by MINI. HAM-D total score >=22, HAM-D item 1 score >=2 at both enrollment and randomization.

Exclusion criteria:
Not reported

Interventions:
Placebo 50-300 mg/days flexible dose for 9 weeks
 vs
Quetiapine 50-300 mg/days flexible dose for 9 weeks

Run-in/wash-out period:
Wash-out: No drug for 28 day(s). Patients still eligible after washout were randomized.

Comorbidities:
None

Timing of outcome assessment: 7, 63 days
Results:
Depression: Change in MADRS (% Remitted) at 9 weeks:
Quetiapine vs Placebo - RR = 2.48 ( 1.70 , 3.62 )

Depression: Change in MADRS (% Responder) at 9 weeks:
Quetiapine vs Placebo - RR = 2.11 ( 1.63 , 2.71 )

Adverse Events:
Placebo vs Quetiapine
“drug-Related Ae”: 39.5%(68/172) vs 62.7%(104/166)
>=7% Weight Decrease: 1.2%(2/172) vs 0.0%(0/166)
>=7% Weight Increase: 0.6%(1/172) vs 0.0%(0/166)
AE Potentially Related To Diabetes (Blood Glucose Increased In Patient Who Was Being Treated For Type II Diabetes Prior To And During The Study): 0.0%(0/172) vs 0.6%(1/166)
AE Potentially Related To Suicidality: 0.6%(1/172) vs 0.6%(1/166)
AEs Potentially Related To Qt Prolongation, Neutropenia/Agranulocytosis, Syncope, Sexual Dysfunction, Or Cerebrovascular Accidents (Eva): 0.0%(0/172) vs 0.0%(0/166)
Abdominal Pain Upper: 2.3%(4/172) vs 3.0%(5/166)
Any AE: 61.0%(105/172) vs 80.7%(134/166)
Asthenia: 0.6%(1/172) vs 3.6%(6/166)
Back Pain: 1.2%(2/172) vs 2.4%(4/166)
Clinically Important Shift To Low Neutrophil Count At End of Treatment: 0.0%(0/172) vs 1.2%(2/166)
Constipation: 2.3%(4/172) vs 6.0%(10/166)
Diarrhea: 7.0%(12/172) vs 5.4%(9/166)
Dizziness: 15.1%(26/172) vs 19.3%(32/166)
Dry Mouth: 10.5%(18/172) vs 20.5%(34/166)
Dysgeusia: 0.6%(1/172) vs 2.4%(4/166)
Edema Peripheral: 2.3%(4/172) vs 0.0%(0/166)
Extrapyramidal Disorder: 0.6%(1/172) vs 3.6%(6/166)
Extrapyramidal Symptoms (EPS) Through The End Of The Study: 2.3%(4/172) vs 9.0%(15/166)
Fatigue: 4.1%(7/172) vs 7.8%(13/166)
Headache: 16.3%(28/172) vs 21.1%(35/166)
Hypertension: 2.3%(4/172) vs 1.2%(2/166)
Hypotension: 0.0%(0/172) vs 2.4%(4/166)
Hypothyroidism: 0.0%(0/172) vs 0.0%(0/166)
Insomnia: 5.8%(10/172) vs 7.8%(13/166)
Nasopharyngitis: 3.5%(6/172) vs 1.2%(2/166)
Nausea: 4.7%(8/172) vs 5.4%(9/166)
Pain In Extremity: 1.2%(2/172) vs 2.4%(4/166)
Sedation: 1.2%(2/172) vs 4.8%(8/166)
Serious AE Leading To Death: 0.0%(0/172) vs 0.0%(0/166)
Serious Ae, All: 1.2%(2/172) vs 2.4%(4/166)
Somnolence: 8.1%(14/172) vs 33.1%(55/166)
Tachycardia: 2.3%(4/172) vs 1.2%(2/166)
Treatment-Emergent Clinically Important Triglyceride Values: 5.8%(10/172) vs 13.9%(23/166)
Treatment-Emergent Hypothyroidism Based On Clinically Important High Thyroid-Stimulating Hormone (Tsh) Values In Combination With Clinically Important Low Thyroxine (T4) Values: 0.0%(0/172) vs 0.0%(0/166)
Treatment-Emergent Shift From <3 To =3 Metabolic Risk Factors: 13.4%(23/172) vs 5.4%(9/166)
Weight Increased: 4.1%(7/172) vs 5.4%(9/166)
Worsening Of Aims Total Score: 4.7%(8/172) vs 9.0%(15/166)
Worsening Of Bars Global Scores: 1.2%(2/172) vs 1.2%(2/166)
Worsening Of Sas Total Score: 8.1%(14/172) vs 13.9%(23/166)
Quetiapine
Extrapyramidal Symptoms (EPS) Only During The Treatment Period: 7.2%(12/166)

Withdrawals:
Placebo vs Quetiapine
Withdrawals:33.7%(58/172) vs 33.7%(56/166)
Withdrawals Due To Adverse Events:4.1%(7/172) vs 9.6%(16/166)
AstraZeneca2007168

Depression

Quetiapine

Location: Canada, Western Europe, Asia, Latin America, South Africa

Trial: AMBER D1448C00004

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Mean: 18

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: NR
Eligible: NR
Entering: 471
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 223

Method of AE assessment: Monitored
Inclusion criteria:
18-65 years old, DSM-IV diagnosis of MDD, HAM-D score >=22, HAM-D item 1 score >=2

Exclusion criteria:
Not reported

Interventions:
Placebo for 9 weeks
 vs
Quetiapine 50-300 mg/days flexible dose for 9 weeks
 vs
Escitalopram 10-20 mg/days flexible dose for 9 weeks

Run-in/wash-out period:
Wash-out: No drug for 7-28 day(s). Patients still eligible after washout were randomized.

Comorbidities:
None

Timing of outcome assessment: 14, 56, 70 days
Results:
Depression: Change in MADRS (% Remitted) at 8 weeks:
Quetiapine vs Placebo - RR = 1.01 ( 0.75 , 1.37 )

Depression: Change in MADRS (% Responder) at 8 weeks:
Quetiapine vs Placebo - RR = 1.18 ( 0.97 , 1.45 )

Adverse Events:
Escitalopram vs Placebo vs Quetiapine
“drug-Related Ae”: 67.5%(106/157) vs 51.6%(81/157) vs 79.6%(125/157)
Abdominal Distension: 3.2%(5/157) vs 2.5%(4/157) vs 2.5%(4/157)
Abdominal Pain: 3.8%(6/157) vs 3.2%(5/157) vs 4.5%(7/157)
Abdominal Pain Upper: 3.2%(5/157) vs 3.8%(6/157) vs 5.7%(9/157)
Akathisia: 3.2%(5/157) vs 0.6%(1/157) vs 1.3%(2/157)
Anxiety: 4.5%(7/157) vs 2.5%(4/157) vs 7.6%(12/157)
Any AE: 80.9%(127/157) vs 72.6%(114/157) vs 86.6%(136/157)
Arthralgia: 0.6%(1/157) vs 3.2%(5/157) vs 5.1%(8/157)
Chills: 0.6%(1/157) vs 0.6%(1/157) vs 3.2%(5/157)
Constipation: 8.3%(13/157) vs 4.5%(7/157) vs 12.7%(20/157)
Cough: 3.2%(5/157) vs 1.3%(2/157) vs 3.2%(5/157)
Deaths: 0.0%(0/157) vs 0.0%(0/157) vs 0.0%(0/157)
Decreased Appetite: 3.2%(5/157) vs 1.9%(3/157) vs 2.5%(4/157)
Diarrhea: 12.1%(19/157) vs 7.0%(11/157) vs 12.1%(19/157)
Dizziness: 18.5%(29/157) vs 14.0%(22/157) vs 33.8%(53/157)
Dry Mouth: 14.0%(22/157) vs 8.3%(13/157) vs 38.2%(60/157)
Dyspepsia: 3.2%(5/157) vs 5.7%(9/157) vs 7.6%(12/157)
Dyspnea: 0.6%(1/157) vs 2.5%(4/157) vs 3.2%(5/157)
Extrapyramidal Disorder: 9.6%(15/157) vs 5.1%(8/157) vs 8.3%(13/157)
Fatigue: 8.9%(14/157) vs 5.1%(8/157) vs 12.1%(19/157)
Gastroenteritis: 0.6%(1/157) vs 3.2%(5/157) vs 1.9%(3/157)
Headache: 31.2%(49/157) vs 31.2%(49/157) vs 26.1%(41/157)
Hot Flush: 4.5%(7/157) vs 1.3%(2/157) vs 3.2%(5/157)
Hyperhidrosis: 7.6%(12/157) vs 5.7%(9/157) vs 5.1%(8/157)
Hypersomnia: 1.3%(2/157) vs 0.6%(1/157) vs 5.7%(9/157)
Increased Appetite: 1.9%(3/157) vs 3.8%(6/157) vs 7.0%(11/157)
Influenza: 1.9%(3/157) vs 2.5%(4/157) vs 5.1%(8/157)
Insomnia: 14.6%(23/157) vs 14.0%(22/157) vs 14.0%(22/157)
Irritability: 5.1%(8/157) vs 5.1%(8/157) vs 5.7%(9/157)
Musculoskeletal Stiffness: 1.9%(3/157) vs 1.9%(3/157) vs 3.2%(5/157)
Myalgia: 7.6%(12/157) vs 3.8%(6/157) vs 7.0%(11/157)
Nasal Congestion: 0.0%(0/157) vs 0.6%(1/157) vs 2.5%(4/157)
Nasopharyngitis: 4.5%(7/157) vs 5.7%(9/157) vs 1.3%(2/157)
Nausea: 29.9%(47/157) vs 19.1%(30/157) vs 21.7%(34/157)
Pain In Extremity: 3.8%(6/157) vs 0.6%(1/157) vs 1.9%(3/157)
Palpitations: 5.1%(8/157) vs 3.8%(6/157) vs 3.8%(6/157)
Paraesthesia: 2.5%(4/157) vs 1.3%(2/157) vs 2.5%(4/157)
Rash: 0.6%(1/157) vs 0.0%(0/157) vs 3.2%(5/157)
Restlessness: 1.9%(3/157) vs 0.6%(1/157) vs 2.5%(4/157)
Sedation: 5.1%(8/157) vs 3.2%(5/157) vs 10.8%(17/157)
Serious Ae Leading To Death: 0.0%(0/157) vs 0.0%(0/157) vs 0.0%(0/157)
Serious Ae, All: 1.9%(3/157) vs 0.6%(1/157) vs 2.5%(4/157)
Somnolence: 8.3%(13/157) vs 3.8%(6/157) vs 35.7%(56/157)
Tachycardia: 0.6%(1/157) vs 0.6%(1/157) vs 4.5%(7/157)
Thirst: 0.6%(1/157) vs 0.0%(0/157) vs 2.5%(4/157)
Vision Blurred: 2.5%(4/157) vs 3.2%(5/157) vs 3.8%(6/157)
Vomiting: 3.8%(6/157) vs 1.9%(3/157) vs 5.7%(9/157)
Weight Increased: 1.3%(2/157) vs 0.0%(0/157) vs 3.8%(6/157)

Withdrawals:
Escitalopram vs Placebo vs Quetiapine
Withdrawals:56.1%(88/157) vs 53.5%(84/157) vs 48.4%(76/157)
Withdrawals Due To Adverse Events:7.0%(11/157) vs 4.5%(7/157) vs 15.9%(25/157)
Bortnick et al. 2011170

Depression

Quetiapine

Location: US

Trial: Opal (D1448C00003)

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 4

Age: Mean: 18

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: 513
Eligible: 310
Entering: 310
Withdrawn: 68
Lost to follow-up: 23
Analyzed: 219

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
18-65 years old, DSM-IV diagnosis of MDD. HAM-D total score >= 22. HAM-D item I >=2

Exclusion criteria:
DSM-IV Axis I disorder other than MDD within 6 months. DSM-IV Axis II disorder major impact, substance abuse, HAM-D item 3 >= 3, severe medical illness, ECG significant depression can be no longer than 12 months or less than 4 weeks.

Interventions:
Placebo for 8 weeks
 vs
Quetiapine 50-300 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Wash-out: Psychotropics for 1-4 week(s) were randomized.

Comorbidities:
None

Timing of outcome assessment: 7, 14, 28, 42, 56, 70 days
Results:
Depression: Change in MADRS (% Remitted) at 8 weeks:
Quetiapine vs Placebo - RR = 1.39 ( 0.97 , 1.98 )

Depression: Change in MADRS (% Responder) at 8 weeks:
Quetiapine vs Placebo - RR = 1.29 ( 1.05 , 1.59 )

Adverse Events:
Excluded from analysis:
Constipation: 1.3%(2/156) vs 5.2%(8/154)
Dizziness: 3.2%(5/156) vs 7.1%(11/154)
Dry Mouth: 6.4%(10/156) vs 32.5%(50/154)
Fatigue: 0.0%(0/156) vs 6.5%(10/154)
Headache: 10.3%(16/156) vs 10.4%(16/154)
Increased Appetite: 1.3%(2/156) vs 6.5%(10/154)
Increased Qtc Interval: 0.0%(0/156) vs 0.0%(0/154)
Madrs Item 10 (Suicidal Thoughts) Score =4: 0.6%(1/156) vs 2.6%(4/154)
Nasal Congestion: 1.9%(3/156) vs 5.2%(8/154)
Nasopharyngitis: 7.1%(11/156) vs 2.6%(4/154)
Nausea: 5.8%(9/156) vs 4.5%(7/154)
Patients Experiencing A =7% Increase In Weight: 1.3%(2/156) vs 2.6%(4/154)
Sedation: 1.9%(3/156) vs 21.4%(33/154)
Sedation Leading To Discontinuation: 0.6%(1/156) vs 3.9%(6/154)
Somnolence: 5.1%(8/156) vs 20.1%(31/154)
Somnolence Leading To Discontinuation: 0.0%(0/156) vs 2.6%(4/154)
Quetiapine XR
Clinically Relevant Differencesin The Mean Change From Baseline To Week 8 In Vital Signs, Hematology, Ecgs Or Clinical Laboratory Parameters.: 0.0%(0/154)

Withdrawals:
Placebo vs Quetiapine XR
Withdrawals:28.8%(45/156) vs 29.9%(46/154)
Withdrawals Due To Adverse Events:2.6%(4/156) vs 8.4%(13/154)
Bissada et al. 2008180

Eating disorder

Olanzapine

Location: Canada

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Single setting

Jadad: 3

Age: Not reported

Sex: 100% Female

Race: Not reported

Screened: 147
Eligible: 76
Entering: 34
Withdrawn: 6
Lost to follow-up: 0
Analyzed: 28

Method of AE assessment: Not reported
Inclusion criteria:
DSM-IV criteria for anorexia or nervosa (restricting or binge / purge subtype) including a body index <= 17.5 kg/m2

Exclusion criteria:
Active suicidal intent, comorbid substance abuse disorder, bipolar disorder, schizophrenia or any other psychotic disorder, organic brain syndromes or dissociative disorders, pregnancy, and failure to use contraception if sexually active

Interventions:
Placebo for 10 weeks
 vs
Olanzapine 2.5-10 mg/days flexible dose for 10 weeks

Run-in/wash-out period:
Run-in: No drug for 2 week(s).

Comorbidities:
Anxiety

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56 days
Results:
Eating Disorder: Change in BMI (BMI) at 4 weeks:
Olanzapine vs Placebo - WMD = 0.11 ( -0.77 , 0.99 )

Eating Disorder: Change in BMI (BMI) at 12 weeks:
Olanzapine vs Placebo - WMD = 0.15 ( -0.80 , 1.10 )

Adverse Events:
Olanzapine vs Placebo
De Novo Development Of Diabetes Mellitus: 0.0%(0/16) vs 0.0%(0/18)
Evidence Of Impaired Glucose Tolerance: 0.0%(0/16) vs 0.0%(0/18)
Serious Adverse Events (Extrapyramidal Symptoms, Excessive Sleepiness, Dizziness Or Galactorrhea): 0.0%(0/16) vs 0.0%(0/18)

Withdrawals:
Olanzapine vs Placebo
Withdrawals:12.5%(2/16) vs 22.2%(4/18)
Brambilla et al. 2007182

Eating disorder

Olanzapine

Location: Western Europe

Trial: Not reported

Funding source: Not reported

Design: RCT only

Setting: Multi-center

Jadad: 2

Age: Not reported

Sex: 100% Female

Race: Not reported

Screened: 35
Eligible: 30
Entering: NR
Withdrawn: 5
Lost to follow-up: 0
Analyzed: 30

Method of AE assessment: Not reported
Inclusion criteria:
Anorexia nervosa per DSM-IV restricted or binging-purging type

Exclusion criteria:
General medical impairments, endocrine, metabolic and immune alterations (other than those limited to anorexia nervosa), cerebral trauma, epilepsy

Interventions:
Placebo for 3 months
 vs
Olanzapine 2.5-5 mg/days fixed titration schedule for 3 months

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety, Depression, OCD, Personality Disorder

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56 days
Results:
Eating Disorder: Change in BMI (BMI) at 4 weeks:
Olanzapine vs Placebo - WMD = -0.00 ( -0.91 , 0.91 )

Eating Disorder: Change in BMI (BMI) at 12 weeks:
Olanzapine vs Placebo - WMD = 0.60 ( -0.55 , 1.75 )
Brambilla et al. 2007183

Eating disorder

Olanzapine

Location: Not reported

Trial: Not reported

Funding source: Hospital

Design: RCT only

Setting: Not reported

Jadad: 2

Age: Not reported

Sex: 100% Female

Race: Not reported

Screened: 20
Eligible: 20
Entering: 20
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Not reported
Inclusion criteria:
Anorexia nervosa according to DSM-IV

Exclusion criteria:
General medical, neuroendorcine, metabolic, immunologic alterations other than these related to AN, axis axis I and II psychopathologies other than AN. Axis I and II psychopathologies other than AN

Interventions:
Placebo for 3 months
 vs
Olanzapine 2.5-5 mg/days fixed titration schedule for 3 months

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 30, 61, 91 days
Results:
Eating Disorder: Change in BMI (BMI) at 4 weeks:
Olanzapine vs Placebo - WMD = -0.20 ( -1.44 , 1.04 )

Eating Disorder: Change in BMI (BMI) at 12 weeks:
Olanzapine vs Placebo - WMD = 0.20 ( -1.05 , 1.45 )
Gaskill et al. 2001184

Eating disorder

Olanzapine

Location: US

Trial: Not reported

Funding source: Not reported

Design: CCT only

Setting: Single setting

Jadad: 0

Age: Not reported

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: NR
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 46

Method of AE assessment: Not reported
Inclusion criteria:
Not reported

Exclusion criteria:
Not reported

Interventions:
Control Group
 vs
Olanzapine 1.25-15 mg/days flexible dose for duration not reported

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: days
Results:
Eating Disorder: Insufficient data to calculate an effect size
Court et al. 2010185

Eating disorder

Quetiapine

Location:
Australia/New Zealand

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Not reported

Sex: 80-99% Female

Race: Not reported

Screened: NR
Eligible: 33
Entering: 33
Withdrawn: 12
Lost to follow-up: 0
Analyzed: 21

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
Diagnosis of AN per DSM-IV, no previous antipsychotic for > 1 week

Exclusion criteria:
Atypical antipsychotic >= 7 days, psychotic illness, history of brain infarct or brain surgery, diabetes, IQ < 70

Interventions:
Other, Treatment as usual 998 Not reported/Not reported frequency not reported for 12 weeks
 vs
Quetiapine 322.5 150-500 mg/days fixed titration schedule for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety, Depression

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 182, 364 days
Results:
Eating Disorder: Change in BMI at 12 weeks:
Quetiapine vs TAU - WMD = -0.10 ( -1.74 , 1.54 )

Adverse Events:
Quetiapine vs Usual tx
Admitted As An Inpatient At A Hospital: 46.7%(7/15) vs 44.4%(8/18)

Withdrawals:
Quetiapine vs Usual tx
Withdrawals:33.3%(5/15) vs 38.9%(7/18)
Withdrawals Due To Adverse Events:13.3%(2/15) vs 0.0%(0/18)
Tassniyom et al. 2010307

Insomnia

Quetiapine

Location: Asia

Trial: Not reported

Funding source: Faculty of Medicine Khon Kean University

Design: RCT only

Setting: Single setting

Jadad: 4

Age: Mean: 25

Sex: 80-99% Female

Race: Not reported

Screened: 25
Eligible: 16
Entering: 16
Withdrawn: 3
Lost to follow-up: 0
Analyzed: 13

Method of AE assessment: Monitored
Inclusion criteria:
16-65, primary insomnia per DSM-IV-TR

Exclusion criteria:
Other psychiatric diagnosis, receiving sedating meds, medical diseases, pregnant, unable to record sleep log, answer questionnaires, or refused

Interventions:
Placebo 25 mg/days fixed single dose for 2 weeks
 vs
Quetiapine 25 mg/days fixed single dose for 2 weeks

Run-in/wash-out period:
Run-in: Psychotropics for 1 week(s). Patients who met the study criteria were randomized.

Comorbidities:
None

Timing of outcome assessment: 14 days
Results:
Insomnia: Change in SL at 2 weeks:
Quetiapine vs Placebo - WMD = -72.43 ( -155.52 , 10.66 )

Insomnia: Change in Sleep Satisfaction at 2 weeks:
Quetiapine vs Placebo - WMD = 5.70 ( -16.95 , 28.35 )

Insomnia: Change in TST at 2 weeks:
Quetiapine vs Placebo - WMD = 52.68 ( -58.13 , 163.49 )
Padala et al. 2006233

PTSD

Risperidone

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Single setting

Jadad: 2

Age: Not reported

Sex: 100% Female

Race: Caucasian, African Ancestry, Mixed

Screened: NR
Eligible: NR
Entering: 20
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 15

Method of AE assessment: Monitored
Inclusion criteria:
PTSD, female, 19-65

Exclusion criteria:
Schizophrenia, bipolar I, unstable illness, suicidality, prior treatment with risperidone, pregnant, nursing, substance abuse / dependency in prior 2 month

Interventions:
Placebo for 10 weeks
 vs
Risperidone 1-6 mg/days flexible dose for 10 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91 days
Results:
PTSD: Insufficient data to calculate an effect size

Withdrawals:
Placebo vs Risperidone
Rash Leading To Withdrawal:0.0%(0/9) vs 9.1%(1/11)
Withdrawals:33.3%(3/9) vs 18.2%(2/11)
Withdrawals Due To Adverse Events:0.0%(0/9) vs 9.1%(1/11)
Rothbaum et al. 2008237

PTSD

Risperidone

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 4

Age: Not reported

Sex: 80-99% Female

Race: Caucasian, African Ancestry, Other-NOS

Screened: 91
Eligible: 25
Entering: 25
Withdrawn: 5
Lost to follow-up: 0
Analyzed: 20

Method of AE assessment: Monitored
Inclusion criteria:
18-65, PTSD due to civilian trauma, CAPS >=50

Exclusion criteria:
Combat related events

Interventions:
Placebo for 8 weeks
 vs
Risperidone 0.5-3 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Run-in: Sertraline for 8 week(s). Non-responders were randomized.

Comorbidities:
Anxiety, Depression

Timing of outcome assessment: 56, 63, 70, 84, 98, 112 days
Results:
PTSD: Change in CAPS at 8 weeks:
Risperidone vs Placebo - WMD = 4.08 ( -10.17 , 18.34 )

PTSD: Change in CAPS at 16 weeks:
Risperidone vs Placebo - WMD = -2.35 ( -18.69 , 13.99 )

Withdrawals:
Placebo vs Risperidone
Withdrawals:0.0%(0/11) vs 35.7%(5/14)
Withdrawals Due To Adverse Events:0.0%(0/11) vs 28.6%(4/14)
Withdrawals Due To Adverse Events Of Elevated Liver Enzyme Levels:0.0%(0/11) vs 7.1%(1/14)
Withdrawals Due To Adverse Events Of Probable Dystonic Reaction Before Given Drug:0.0%(0/11) vs 7.1%(1/14)
Withdrawals Due To Adverse Events Of Tachycardia:0.0%(0/11) vs 7.1%(1/14)
Withdrawals Due To Adverse Events Of Visiting ER Twice With Unremitting Chest Pain:0.0%(0/11) vs 7.1%(1/14)
Hamner et al. 2009239

PTSD

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 2

Age: Not reported

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: NR
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
18-65 years old, DSM-IV diagnosis of PTSD, CAPS symptom status version >=50

Exclusion criteria:
A history of sensitivity to quetiapine, substance abuse, schizophrenia, schizoaffective disorder, bipolar disorder, dementia

Interventions:
Placebo for 12 weeks
 vs
Quetiapine 258 (25-800) mg/days flexible dose for 12 weeks

Run-in/wash-out period:
Wash-out: Placebo for 1 week(s) were randomized.

Comorbidities:
None

Timing of outcome assessment: 84 days
Results:
PTSD: Insufficient data to calculate an effect size
Nickel et al. 2007219

Personality disorder

Aripiprazole

Location: Western Europe

Trial: Not reported

Funding source: Not funded

Design: RCT only

Setting: Not reported

Jadad: 2

Age: Mean: 22

Sex: 80-99% Female

Race: Not reported

Screened: 52
Eligible: 52
Entering: 52
Withdrawn: 13
Lost to follow-up: 0
Analyzed: 39

Method of AE assessment: Not reported
Inclusion criteria:
Same as ID 2754

Exclusion criteria:
Schizophrenia, current use of psychotic medication in previous placebo group, termination of aripiprazole, current psychotherapy, pregnancy, suicide ideation, severe somatic illness, substance abuse

Interventions:
Placebo for 18 months
 vs
Aripiprazole 15 mg/days fixed single dose for 18 months

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety, Depression, OCD

Timing of outcome assessment: 182, 365, 547 days
Results:
Personality Disorder: Change in SCL-90 (GSI) at 72 weeks:
Aripiprazole vs Placebo - WMD = -16.50 ( -20.51 , -12.49 )

Adverse Events:
Aripiprazole vs Placebo
Anxiety: 15.4%(4/26) vs 19.2%(5/26)
Constipation: 15.4%(4/26) vs 11.5%(3/26)
Headache: 34.6%(9/26) vs 30.8%(8/26)
Insomnia: 30.8%(8/26) vs 23.1%(6/26)
Nausea: 15.4%(4/26) vs 15.4%(4/26)
Numbness: 11.5%(3/26) vs 3.8%(1/26)
Restlessness: 11.5%(3/26) vs 7.7%(2/26)
Significant Weight Change: 0.0%(0/26) vs 0.0%(0/26)

Withdrawals:
Aripiprazole vs Placebo
Withdrawals:15.4%(4/26) vs 34.6%(9/26)
Pascual et al. 2008222

Personality disorder

Ziprasidone

Location: Western Europe

Trial: Not reported

Funding source: Government, Industry, REM-TAP Network

Design: RCT only

Setting: Single setting

Jadad: 3

Age: Not reported

Sex: 80-99% Female

Race: Not reported

Screened: 127
Eligible: 65
Entering: 60
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 29

Method of AE assessment: Monitored
Inclusion criteria:
Borderline personality disorder, 18-45, CGI-5 >= 4, contraception in females

Exclusion criteria:
Comorbidity, schizophrenia, drug-induced psychosis, organic brain syndrome, alcohol or other substance dependence, bipolar, mental retardation, major depressive episode

Interventions:
Placebo for 12 weeks
 vs
Ziprasidone 40-200 mg/days flexible dose for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 14, 28, 42, 56, 70, 84 days
Results:
Personality Disorder: Change in SCL-90-R (GSI) at 14 weeks:
Ziprasidone vs Placebo - WMD = 0.18 ( -0.35 , 0.71 )

Adverse Events:
Placebo vs Ziprasidone
Dizziness: 0.0%(0/30) vs 13.3%(4/30)
Gastrointestinal Symptoms: 6.7%(2/30) vs 0.0%(0/30)
Headache: 3.3%(1/30) vs 0.0%(0/30)
Hyperprolactinemia Not Clinically Relevant: 0.0%(0/30) vs 6.7%(2/30)
Minor Sedation: 3.3%(1/30) vs 20.0%(6/30)
Movement Disorders, Dystonia, Akathisia, Rigidity Or Hyperkinesia: 0.0%(0/30) vs 0.0%(0/30)
Serious Adverse Events: 0.0%(0/30) vs 0.0%(0/30)
Significant Changes In Weight Or Blood Pressure: 0.0%(0/30) vs 0.0%(0/30)
Treatment-Emergent Adverse Events: 13.3%(4/30) vs 36.7%(11/30)
Uneasy Feeling: 0.0%(0/30) vs 10.0%(3/30)

Withdrawals:
Placebo vs Ziprasidone
Withdrawals:46.7%(14/30) vs 56.7%(17/30)
Withdrawals Due To Adverse Events:0.0%(0/30) vs 30.0%(9/30)
Withdrawals Due To Adverse Events Of Needed Psychiatric
Hospitalization:10.0%(3/30) vs 13.3%(4/30)
Withdrawals Due To Treatment-Emergent Adverse Events:0.0%(0/30) vs 13.3%(4/30)
McClure et al. 2009227

Personality disorder

Risperidone

Location: US

Trial: Not reported

Funding source: Government, Industry

Design: RCT only

Setting: Multi-center

Jadad: 4

Age: Not reported

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: 31
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 20

Method of AE assessment: Not reported
Inclusion criteria:
18-60, schizotypal personality disorder

Exclusion criteria:
Not reported

Interventions:
Placebo for 10 weeks
 vs
Risperidone 0.25-2 mg/days fixed titration schedule for 10 weeks

Run-in/wash-out period:
Run-in: Placebo for 2 week(s).
Symptomatically stable patients were randomized.

Comorbidities:
None

Timing of outcome assessment: 42, 84 days
Results:
Personality Disorder: Change in PANSS (negative) at 12 weeks:
Risperidone vs Placebo - WMD = -1.00 ( -6.50 , 4.50 )

Personality Disorder: Change in PANSS (postive) at 12 weeks:
Risperidone vs Placebo - WMD = -1.70 ( -5.80 , 2.40 )

Personality Disorder: Change in PANSS (general) at 12 weeks:
Risperidone vs Placebo - WMD = -1.80 ( -9.68 , 6.08 )

Withdrawals:
Placebo vs Risperidone
Galactorrhea (Leading To Withdrawal):0.0%(0/12) vs 5.3%(1/19)
Increase In Suicidal Ideation (Leading To Withdrawal):0.0%(0/12) vs 5.3%(1/19)
Withdrawals:25.0%(3/12) vs 42.1%(8/19)
Risperidone
Withdrawals Due To Adverse Events:10.5%(2/19)
Schulz et al. 2008223

Personality disorder

Olanzapine

Location: US, UK, Western Europe

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Not reported

Sex: Mixed

Race: Caucasian, Other-NOS

Screened: 385
Eligible: 314
Entering: 314
Withdrawn: 119
Lost to follow-up: 17
Analyzed: 175

Method of AE assessment: Monitored
Inclusion criteria:
18-65, DSM-IV for personality disorder and DSM-IV for borderline personality disorder by DIPD-IV, ZAN-BPD = q at randomization

Exclusion criteria:
Schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar I, delusional disorder by DSM-IV Axis I, major depressive disorder, bipolar II, substance dependence within 3 month, actively suicidal PTSD, panic disorder, OCD BMI < 17, cluster A personality disorder.

Interventions:
Placebo for 12 weeks
 vs
Olanzapine 2.5-20 mg/days flexible dose for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 28, 42, 56, 70, 84 days
Results:
Personality Disorder: Change in SCL-90-R (GSI) at 12 weeks:
Olanzapine vs Placebo - WMD = -0.04 ( -0.31 , 0.23 )

Adverse Events:
Olanzapine vs Placebo
Aggression: 0.6%(1/155) vs 1.3%(2/159)
Agitation: 0.6%(1/155) vs 0.0%(0/159)
Alcoholism: 0.6%(1/155) vs 0.0%(0/159)
Anxiety: 4.5%(7/155) vs 5.0%(8/159)
Appetite Increased: 17.4%(27/155) vs 7.5%(12/159)
Deaths During Study: 0.0%(0/155) vs 0.0%(0/159)
Depressed Mood: 0.0%(0/155) vs 0.6%(1/159)
Drug Misuse: 0.6%(1/155) vs 0.0%(0/159)
Dry Mouth: 7.1%(11/155) vs 3.8%(6/159)
Exacerbation Of Borderline Personality Disorder Symptoms: 0.0%(0/155) vs 1.3%(2/159)
Fatigue: 10.3%(16/155) vs 7.5%(12/159)
Headache: 14.8%(23/155) vs 11.3%(18/159)
Impulsive Behavior: 0.6%(1/155) vs 0.0%(0/159)
Incidence Of Treatment-Emergent Abnormal High Levels Of Prolactin At Endpoint: 19.4%(30/155) vs 8.8%(14/159)
Insomnia: 2.6%(4/155) vs 6.3%(10/159)
Nausea: 4.5%(7/155) vs 7.5%(12/159)
Participants With >=1 Treatment-Emergent Adverse Event: 65.8%(102/155) vs 56.6%(90/159)
Sedation: 11.6%(18/155) vs 1.3%(2/159)
Self-Injurious Ideation: 0.6%(1/155) vs 0.0%(0/159)
Self-Mutilation: 0.6%(1/155) vs 0.0%(0/159)
Serious AE: 3.9%(6/155) vs 5.7%(9/159)
Somnolence: 12.9%(20/155) vs 4.4%(7/159)
Suicidal Ideation: 5.8%(9/155) vs 2.5%(4/159)
Treatment-Emergent Weight Gain =7% Of Baseline: 32.9%(51/155) vs 2.5%(4/159)
Weight Decrease: 0.0%(0/155) vs 0.6%(1/159)
Weight Increased: 17.4%(27/155) vs 2.5%(4/159)

Withdrawals:
Olanzapine vs Placebo
Withdrawals:48.4%(75/155) vs 38.4%(61/159)
Withdrawals Due To Adverse Events:11.0%(17/155) vs 11.3%(18/159)
Linehan et al. 2008224

Personality disorder

Olanzapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Not reported

Sex: 100% Female

Race: Caucasian, African Ancestry, Hispanic, Native American, Other-NOS

Screened: 44
Eligible: 24
Entering: 24
Withdrawn: 8
Lost to follow-up: 0
Analyzed: 16

Method of AE assessment: Not reported
Inclusion criteria:
Borderline, personality disorder according to personality disorder and conducted clinical interview for DSM-IV (SCID-II), borderline personality disorder for inappropriate anger on the SCID II, OAS-M irritability subscale >=6.

Exclusion criteria:
Schizophrenia, bipolar I, schizoaffective disorder, major depressive disorder with psychotic features or other psychotic disorder, mental or seizure disorder, substance dependence in the past 6 month according to DSM-IV, self-inflicted injury in the 8 weeks prior, pregnant, breast feeding or planning to be pregnant.

Interventions:
Placebo 2.5-15 mg/days flexible dose for duration not reported
 vs
Olanzapine 2.5-15 mg/days flexible dose for duration not reported

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety, Depression, Personality Disorder, Substance Abuse, Eating Disorder

Timing of outcome assessment: 49, 98, 147 days
Results:
Personality Disorder: Insufficient data to calculate an effect size

Adverse Events:
Olanzapine vs Placebo
Dizziness: 133.3%(16/12) vs 66.7%(8/12)
Muscle Stiffness: 166.7%(20/12) vs 83.3%(10/12)
Severe Nervousness: 0.0%(0/12) vs 83.3%(10/12)
Sexual Dysfunction: 66.7%(8/12) vs 0.0%(0/12)
Significantly Distressing Or Incapacitating Sedation: 83.3%(10/12) vs 16.7%(2/12)
Weight Gain: 183.3%(22/12) vs 116.7%(14/12)

Withdrawals:
Olanzapine vs Placebo
Withdrawals:33.3%(4/12) vs 33.3%(4/12)
van den Broek et al. 2008221

Personality disorder

Quetiapine

Location: Western Europe

Trial: Not reported

Funding source: Not reported

Design: RCT only

Setting: Not reported

Jadad: 1

Age: Not reported

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: 24
Withdrawn: 8
Lost to follow-up: NR
Analyzed: 16

Method of AE assessment: Not reported
Inclusion criteria:
DSM-IV diagnosis of borderline personality disorder

Exclusion criteria:
Schizophrenia, current major depression, bipolar disorder, substance dependence

Interventions:
Placebo for 8 weeks
 vs
Quetiapine 200-600 mg/days flexible dose for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 28, 42, 56, 70 days
Results:
Personality Disorder: Insufficient data to calculate an effect size
Zanarini et al. 2007220

Personality disorder

Olanzapine

Location: Not reported

Trial: Not reported

Funding source: Not reported

Design: RCT only

Setting: Not reported

Jadad: 2

Age: Not reported

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: 451
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Not reported
Inclusion criteria:
18-65 years old, diagnosis of DSM-IV BPD

Exclusion criteria:
Not reported

Interventions:
Placebo for 12 weeks
 vs
Olanzapine 2.5 mg/days frequency not reported for 12 weeks
 vs
Olanzapine 5-10 mg/days frequency not reported for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 84 days
Results:
Personality Disorder: Change in Zanarini Rating Scale (Response Rate) at 12 weeks:
Olanzapine 2.5mg/d vs Placebo - RR = 1.04 ( 0.86 , 1.26 )

Personality Disorder: Change in Zanarini Rating Scale (Response Rate) at 12 weeks:
Olanzapine 5-10mg/d vs Placebo - RR = 1.28 ( 1.08 , 1.51 )
Kampman et al. 2007259

Substance abuse

Quetiapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Mean: 47

Sex: Mixed

Race: Caucasian, Other-NOS

Screened: 87
Eligible: 72
Entering: 61
Withdrawn: 5
Lost to follow-up: 6
Analyzed: 61

Method of AE assessment: Monitored, elicited by investigator
Inclusion criteria:
Aged >= 18 years old, alcohol dependence, have a consecutive 30 days period drinking at least 48 standard drinks, >= 2 days of heavy drinking, >= 3 consecutive days of abstinence, Clinical Institutes Withdrawal Assessment for Alcohol score < 8.

Exclusion criteria:
Diagnosis of any psychoactive substance dependence other than alcohol or nicotine, current use of psychoactive drugs, taking psychotropic medications, current, severe psychiatric symptoms, severe medical illness, history of seizures or severe head trauma.

Interventions:
Placebo 50-400 mg/days fixed titration schedule for 12 weeks
 vs
Quetiapine 50-400 mg/days fixed titration schedule for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety, Depression, OCD, Personality Disorder, PTSD

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56 days
Results:
Substance Abuse: Change in Complete Abstinence (Alcohol) at 12 weeks:
Quetiapine vs Placebo - RR = 4.97 ( 1.17 , 21.11 )

Adverse Events:
Quetiapine vs Placebo
Aches And Pains: 44.8%(13/29) vs 56.3%(18/32)
Dry Mouth: 31.0%(9/29) vs 0.0%(0/32)
Dysphoria: 31.0%(9/29) vs 21.9%(7/32)
Gastrointestinal Complaints: 41.4%(12/29) vs 37.5%(12/32)
Headache: 27.6%(8/29) vs 28.1%(9/32)
Insomnia: 3.4%(1/29) vs 18.8%(6/32)
Lightheaded: 17.2%(5/29) vs 12.5%(4/32)
Sedation: 51.7%(15/29) vs 18.8%(6/32)
Skin Rash: 10.3%(3/29) vs 3.1%(1/32)
Upper Respiratory Tract Infection: 37.9%(11/29) vs 31.3%(10/32)

Withdrawals:
Quetiapine vs Placebo
Withdrawals:20.7%(6/29) vs 25.0%(8/32)
Withdrawals Due To Adverse Events:0.0%(0/29) vs 3.1%(1/32)
Loebl et al. 2008269

Substance abuse

Risperidone

Location: US

Trial: Not reported

Funding source: Government, Industry

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Not reported

Sex: 100% Male

Race: Caucasian, African Ancestry

Screened: 89
Eligible: 31
Entering: 31
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 14

Method of AE assessment: Monitored
Inclusion criteria:
Men, 18-60, cocaine dependence, using cocaine >=1 every other week

Exclusion criteria:
Schizophrenia, bipolar disorder, MDD, HIV, head trauma with loss of consciousness, unstable medical condition

Interventions:
Placebo for 12 weeks
 vs
Risperidone 1-2 mg pills daily fixed titration schedule and 25mg injection biweekly fixed dose for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
Anxiety, Depression, Substance Abuse

Timing of outcome assessment: 7, 14, 21, 35, 49, 63, 77 days
Results:
Substance Abuse: Change in ASI (Drug Composite) at 12 weeks:
Risperidone vs Placebo - WMD = -0.03 ( -0.09 , 0.03 )

Withdrawals:
Placebo vs Risperidone
Withdrawals:60.0%(9/15) vs 50.0%(8/16)
Withdrawals Due To Adverse Events:0.0%(0/15) vs 12.5%(2/16)
Anton et al. 2008252

Substance abuse

Aripiprazole

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Mean: 47

Sex: Mixed

Race: Caucasian, African Ancestry, Asian/Pacific Islander, Other-NOS

Screened: 691
Eligible: 295
Entering: 295
Withdrawn: 75
Lost to follow-up: 25
Analyzed: 195

Method of AE assessment: Monitored
Inclusion criteria:
21-65 years old, alcohol dependence, presents at 3 visits with negative breathalyzer results and abstain from alcohol before randomization score < 8 on Clinical Institute Withdrawal Assessment for Alcohol Revised

Exclusion criteria:
Substance abuse on drugs other than cocaine and opiates with exception of marijuana abuse within past year, pregnant, axis I or II disorder, high suicidal risk, allergy to aripiprazole taking an investigational agent within past month.

Interventions:
Placebo 27.4 mg/days average final dose for 12 weeks
 vs
Aripiprazole 2-30 mg/days fixed titration schedule for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 28, 56, 84 days
Results:
Substance Abuse: Change in Complete Abstinence (Alcohol) at 12 weeks:
Aripiprazole vs Placebo - RR = 0.50 ( 0.29 , 0.88 )

Substance Abuse: Change in Abstinent Days (Alcohol) at 12 weeks:
Aripiprazole vs Placebo - SMD = -0.13 ( -0.36 , 0.10 )

Adverse Events:
Aripiprazole vs Placebo
Anxiety: 12.8%(19/149) vs 2.7%(4/146)
Clinically Significant Alt Elevations (Alt [sgpt]=3× Upper Limit Of Normal): 3.4%(5/149) vs 0.0%(0/146)
Clinically Significant Ast Elevations (Ast [sgot]=3× Upper Limit Of Normal): 2.7%(4/149) vs 1.4%(2/146)
Death: 0.0%(0/149) vs 0.0%(0/146)
Diarrhea: 6.7%(10/149) vs 5.5%(8/146)
Disturbance In Attention: 9.4%(14/149) vs 2.1%(3/146)
Dizziness: 7.4%(11/149) vs 7.5%(11/146)
EPS-Related AE: Akathisia: 6.0%(9/149) vs 0.7%(1/146)
EPS-Related AE: Dyskinesia: 1.3%(2/149) vs 0.0%(0/146)
EPS-Related AE: Tremor: 3.4%(5/149) vs 2.7%(4/146)
EPS-Related AEs: 9.4%(14/149) vs 3.4%(5/146)
Fatigue: 24.2%(36/149) vs 6.8%(10/146)
Headache: 20.1%(30/149) vs 24.0%(35/146)
Increased Appetite: 5.4%(8/149) vs 2.7%(4/146)
Insomnia: 21.5%(32/149) vs 11.0%(16/146)
Nausea: 6.7%(10/149) vs 6.8%(10/146)
Restlessness: 18.1%(27/149) vs 2.7%(4/146)
Serious AE: 2.7%(4/149) vs 2.7%(4/146)
Serious AE: Accidental Overdose: 0.0%(0/149) vs 0.7%(1/146)
Serious AE: Atrial Fibrillation: 0.0%(0/149) vs 0.7%(1/146)
Serious AE: Cellulitis: 0.7%(1/149) vs 0.0%(0/146)
Serious AE: Chest Pain: 0.7%(1/149) vs 0.0%(0/146)
Serious AE: Migraine: 0.7%(1/149) vs 0.0%(0/146)
Serious AE: Overdose (Not Accidental): 0.0%(0/149) vs 0.7%(1/146)
Serious AE: Thrombosis: 0.7%(1/149) vs 0.0%(0/146)
Serious AE: Worsening Alcoholism: 0.0%(0/149) vs 0.7%(1/146)
Somnolence: 16.8%(25/149) vs 5.5%(8/146)
Treatment Related AE: 81.2%(121/149) vs 61.6%(90/146)
Used Anticholinergic For Potential EPS: 2.7%(4/149) vs 0.0%(0/146)
Withdrawals:
Aripiprazole
Anxiety Leading To Withdrawal:3.4%(5/149)
Insomnia Leading To Withdrawal:6.7%(10/149)
Restlessness Leading To Withdrawal:2.7%(4/149)
Aripiprazole vs Placebo
Withdrawals:40.9%(61/149) vs 26.7%(39/146)
Withdrawals Due To Adverse Events:14.1%(21/149) vs 0.7%(1/146)
Grabowski et al.2000266

Substance abuse

Risperidone

Location: US

Trial: Not reported

Funding source: Government

Design: RCT only

Setting: Not reported

Jadad: 4

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic

Screened: 193
Eligible: NR
Entering: NR
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
Not reported

Exclusion criteria:
Not reported

Interventions:
Placebo for 12 weeks
 vs
Risperidone 2 mg/days fixed single dose for 12 weeks
 vs
Risperidone 4 mg/days fixed single dose for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 days
Results:
Substance Abuse: Insufficient data to calculate an effect size
Grabowski et al. 2004274

Substance abuse

Risperidone

Location: US

Trial: Not reported

Funding source: Government

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic

Screened: 120
Eligible: NR
Entering: 96
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
18-50, dual dependent (cocaine and heroin) good medical health, without other psych diagnosis (except nicotine dependence)

Exclusion criteria:
Not reported

Interventions:
Placebo for 26 weeks
 vs
Risperidone 2 mg/days frequency not reported for 26 weeks
 vs
Risperidone 4 mg/days frequency not reported for 26 weeks

Run-in/wash-out period:
Wash-out: Risperidone stabilization for 2 weeks. Patients in symptomatic remission were randomized.

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91, 98, 105, 112, 119, 126, 133, 140, 147, 154, 161, 168 days
Results:
Substance Abuse: Insufficient data to calculate an effect size

Withdrawals:
Placebo vs Risperidone 2mg vs Risperidone 4mg
Withdrawals:78.8%(26/33) vs 65.6%(21/32) vs 54.8%(17/31)
Guardia et al. 2004256

Substance abuse

Olanzapine

Location: Western Europe

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Single setting

Jadad: 5

Age: Not reported

Sex: Mixed

Race: Not reported

Screened: NR
Eligible: 60
Entering: 60
Withdrawn: 19
Lost to follow-up: 0
Analyzed: 41

Method of AE assessment: Monitored
Inclusion criteria:
DSM-IV for alcohol dependence disorder age 18 - 60

Exclusion criteria:
Pregnancy, breast feeding, severe organic disorder, AST or ALT > 150 units /l, severe psychiatric disorders or psychotic disorders, bipolar I, severe major depressive disorder with suicidal risk, severe personality disorder, other current substance abuse or dependence disorder (except for nicotine) that was not in sustained remission, and less than 5 or more than 30 days since the last drink.

Interventions:
Placebo for 12 weeks
 vs
Olanzapine 5-15 mg/days flexible dose for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 42, 56, 70, 84 days
Results:
Substance Abuse: Change in Abstinent Days (Alcohol) at 12 weeks:
Olanzapine vs Placebo - SMD = -0.35 ( -0.86 , 0.16 )

Adverse Events:
Olanzapine vs Placebo
Amenorrhea: 3.4%(1/29) vs 3.2%(1/31)
Anxiety: 3.4%(1/29) vs 12.9%(4/31)
Appetite Increase: 24.1%(7/29) vs 9.7%(3/31)
Constipation: 10.3%(3/29) vs 9.7%(3/31)
Decreased Sexual Desire: 3.4%(1/29) vs 12.9%(4/31)
Delayed Ejaculation: 3.4%(1/29) vs 6.5%(2/31)
Depression: 6.9%(2/29) vs 9.7%(3/31)
Dizziness: 0.0%(0/29) vs 9.7%(3/31)
Drowsiness: 17.2%(5/29) vs 16.1%(5/31)
Dry Mouth: 10.3%(3/29) vs 6.5%(2/31)
Erection Difficulty: 3.4%(1/29) vs 6.5%(2/31)
Hypokinesia: 3.4%(1/29) vs 3.2%(1/31)
Itching: 3.4%(1/29) vs 0.0%(0/31)
Loss Of Energy: 6.9%(2/29) vs 12.9%(4/31)
Motor Tension: 0.0%(0/29) vs 9.7%(3/31)
Muscle Stiffness: 3.4%(1/29) vs 0.0%(0/31)
Orthostatic Hypotension: 3.4%(1/29) vs 12.9%(4/31)
Photosensitivity: 6.9%(2/29) vs 3.2%(1/31)
Tremor: 3.4%(1/29) vs 3.2%(1/31)
Weight Gain: 31.0%(9/29) vs 12.9%(4/31)

Withdrawals:
Olanzapine vs Placebo
Withdrawals:41.4%(12/29) vs 22.6%(7/31)
Withdrawals Due To Adverse Events:0.0%(0/29) vs 3.2%(1/31)
Hamilton et al. 2009263

Substance abuse

Olanzapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Single setting

Jadad: 4

Age: Mean: 33

Sex: 100% Male

Race: Caucasian, African Ancestry

Screened: NR
Eligible: 48
Entering: 52
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
Age >= 18, cocaine dependence according to DSM-V, active use of cocaine within 30 days by urine test or self-report

Exclusion criteria:
Currently receiving antipsychotic medication, current DSM - IV diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder. current active psychotic symptoms, hallucinations, remarkably disorganized speech, history of bipolar disorder, major depressive disorder by hypersensitivity to olanzapine serious unstable medical illness.

Interventions:
Placebo 2.5-20 mg/days flexible dose for 16 weeks
 vs
Olanzapine 2.5-20 mg/days flexible dose for 16 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
Depression, OCD, PTSD

Timing of outcome assessment: 7, 14, 21, 28, 42, 56, 70, 84 days
Results:
Substance Abuse: Insufficient data to calculate an effect size

Adverse Events:
Olanzapine vs Placebo
Abdominal Pain: 13.0%(3/23) vs 20.0%(5/25)
Akathisia: 39.1%(9/23) vs 28.0%(7/25)
Amnesia: 21.7%(5/23) vs 4.0%(1/25)
Any Side Effect: 100.0%(23/23) vs 96.0%(24/25)
Articulation Impairment: 17.4%(4/23) vs 20.0%(5/25)
Asthenia: 26.1%(6/23) vs 16.0%(4/25)
Blepharitis: 8.7%(2/23) vs 4.0%(1/25)
Chest Pain: 8.7%(2/23) vs 28.0%(7/25)
Constipation: 26.1%(6/23) vs 40.0%(10/25)
Dizziness: 21.7%(5/23) vs 16.0%(4/25)
Dry Mouth: 69.6%(16/23) vs 44.0%(11/25)
Euphoria: 13.0%(3/23) vs 12.0%(3/25)
Increased Appetite: 87.0%(20/23) vs 60.0%(15/25)
Muscle Twitching: 30.4%(7/23) vs 28.0%(7/25)
Neck Rigidity: 26.1%(6/23) vs 28.0%(7/25)
Non-Aggressive Behavior Changes: 26.1%(6/23) vs 28.0%(7/25)
Peripheral Edema: 8.7%(2/23) vs 4.0%(1/25)
Postural Hypotension: 52.2%(12/23) vs 28.0%(7/25)
Rash: 8.7%(2/23) vs 4.0%(1/25)
Somnolence: 73.9%(17/23) vs 56.0%(14/25)
Stuttering: 17.4%(4/23) vs 20.0%(5/25)
Tachycardia: 8.7%(2/23) vs 20.0%(5/25)
Tremor: 17.4%(4/23) vs 20.0%(5/25)
Weight Gain: 69.6%(16/23) vs 64.0%(16/25)
Hutchison et al. 2006257

Substance abuse

Olanzapine

Location: US

Trial: Not reported

Funding source: Government, Industry

Design: RCT only

Setting: Single setting

Jadad: 1

Age: Not reported

Sex: Mixed

Race: Caucasian

Screened: 154
Eligible: 78
Entering: 64
Withdrawn: 13
Lost to follow-up: 0
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
Excellent health - DSM - IV for alcohol dependence

Exclusion criteria:
Psychiatric diagnosis (bipolar disorder, schizophrenia, bulimia, anorexia nervosa) psychological disorder, recurring pharmacotherapy, endorsed current use of illicit drugs other than marijuana, or tested positive for the use of illicit drugs

Interventions:
Placebo 2.5-5 mg/days fixed single dose for 12 weeks
 vs
Olanzapine 2.5-5 mg/days fixed titration schedule for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 14, 28, 56, 84 days
Results:
Substance Abuse: Insufficient data to calculate an effect size

Withdrawals:
Olanzapine vs Placebo
Withdrawals:18.2%(6/33) vs 22.6%(7/31)
Kampman et al. 2003264

Substance abuse

Olanzapine

Location: US

Trial: Not reported

Funding source: Industry

Design: RCT only

Setting: Single setting

Jadad: 4

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry, Native American

Screened: NR
Eligible: NR
Entering: 30
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 27

Method of AE assessment: Monitored
Inclusion criteria:
$100 worth of cocaine use in prior month, age 18-60 cocaine dependency

Exclusion criteria:
Substance dependency besides nicotine and alcohol, severe alcohol dependence, psychosis, dementia, use of other psychotropic medications, unstable medical illness, history of hypersensitivity to olanzapine

Interventions:
Placebo 2.5-10 mg/days fixed titration schedule for 11 weeks
 vs
Olanzapine 2.5-10 mg/days fixed titration schedule for 11 weeks

Run-in/wash-out period:
Run-in: Psychosocial treatment for 1 week(s).
Eligible participants were randomized.

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 days
Results:
Substance Abuse: Change in ASI (Drug Composite) at 12 weeks:
Olanzapine vs Placebo - WMD = 0.03 ( -0.03 , 0.09 )

Adverse Events:
Olanzapine vs Placebo
Medication Related Serious AE: 0.0%(0/15) vs 0.0%(0/15)

Withdrawals:
Olanzapine vs Placebo
Withdrawals:13.3%(2/15) vs 6.7%(1/15)
Levin et al. 1999268

Substance abuse

Risperidone

Location: US

Trial: Not reported

Funding source: Government

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic

Screened: NR
Eligible: 14
Entering: 14
Withdrawn: 4
Lost to follow-up: 0
Analyzed: 10

Method of AE assessment: Monitored
Inclusion criteria:
Cocaine dependence

Exclusion criteria:
Alcohol, opiate or sedative dependence, MD on dysthymia, axis I disorder requiring treatment

Interventions:
Placebo for 6 weeks
 vs
Risperidone 1-6 mg/days frequency not reported for 12 weeks

Run-in/wash-out period:
Run-in: Placebo for 2 week(s).

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 3, 7 days
Results:
Substance Abuse: Change in Reduction in Use (Urine) at 6 weeks:
Risperidone vs Placebo - WMD = 0.10 ( -0.22 , 0.42 )
Lile et al. 2008261

Substance abuse

Aripiprazole

Location: US

Trial: Not reported

Funding source: Government

Design: CCT only

Setting: Single setting

Jadad: 1

Age: Not reported

Sex: 80-99% Male

Race: Caucasian, African Ancestry

Screened: 12
Eligible: 12
Entering: 24
Withdrawn: 6
Lost to follow-up: 0
Analyzed: 12

Method of AE assessment: Monitored
Inclusion criteria:
Cocaine dependence, no other psychiatric diagnosis

Exclusion criteria:
Not reported

Interventions:
Placebo for 10 days
 vs
Aripiprazole 15 mg/days fixed single dose for 10 days

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: days
Results:
Substance Abuse: Insufficient data to calculate an effect size

Adverse Events:
Aripiprazole
Extrapyramidal Symptoms During Maintenance: 8.3%(1/12)

Withdrawals:
Aripiprazole
Withdrawals:50.0%(6/12)
Withdrawals Due To Adverse Events:8.3%(1/12)
Newton et al. 2008272

Substance abuse

Aripiprazole

Location: US

Trial: Not reported

Funding source: Government

Design: RCT only

Setting: Multi-center

Jadad: 3

Age: Mean: 30

Sex: 80-99% Male

Race: Caucasian, African Ancestry, Hispanic

Screened: NR
Eligible: NR
Entering: NR
Withdrawn: NR
Lost to follow-up: NR
Analyzed: 16

Method of AE assessment: Monitored
Inclusion criteria:
Methamphetamine dependent, not seeking treatment, aged 18-45, had normal physical examinations, EKG's and clinical lab assessments.

Exclusion criteria:
History of asthma, pregnancy, prior adverse reaction to methamphetamine or aripiprazole, history of seizure disorder, head trauma, dependent on other drugs (except nicotine), other axis I psychiatric disorder

Interventions:
Placebo for 14 days
 vs
Aripiprazole 15 mg/days fixed single dose for 14 days

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 14 days
Results:
Substance Abuse: Change in BDI at 2 weeks:
Aripiprazole vs Placebo - WMD = 3.62 ( -4.29 , 11.53 )

Adverse Events:
Aripiprazole vs Placebo
At Least One AE: 87.5%(7/8) vs 75.0%(6/8)
Restlessness: 37.5%(3/8) vs 0.0%(0/8)
Severe AE: 25.0%(2/8) vs 12.5%(1/8)
Tremor: 50.0%(4/8) vs 25.0%(2/8)

Withdrawals:
Aripiprazole vs Placebo
Withdrawals:0.0%(0/8) vs 0.0%(0/8)
Reid et al. 2005265

Substance abuse

Olanzapine

Location: US

Trial: Not reported

Funding source: Government

Design: RCT only

Setting: Multi-center, VA Healthcare System

Jadad: 1

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry, Hispanic, Other-NOS

Screened: 135
Eligible: 68
Entering: NR
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
Standardized MDD CREST study inclusion criteria

Exclusion criteria:
Clinically significant medical condition, standardized MDD CREST study exclusion criteria

Interventions:
Placebo 2 tablets/days fixed single dose for 8 weeks
 vs
Olanzapine 5-10 mg/days fixed titration schedule for 8 weeks
 vs
Valproate 800-1500 mg/days fixed titration schedule for 8 weeks
 vs
Other, Carnitine + Carnitine + CoQ 10 200+500 mg/days fixed single dose for 8 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14, 21, 28, 35, 42, 49, 56 days
Results:
Substance Abuse: Change in ASI (Drug Composite) at 8 weeks:
Olanzapine vs Placebo - WMD = 0.02 ( -0.23 , 0.27 )

Adverse Events:
Carnitine+CoQ10 vs Olanzapine vs Placebo vs Valproate
Abdominal Pain: 12.5%(2/16) vs 5.6%(1/18) vs 6.3%(1/16) vs 27.8%(5/18)
Anxiety: 0.0%(0/16) vs 0.0%(0/18) vs 0.0%(0/16) vs 11.1%(2/18)
Arthralgia: 6.3%(1/16) vs 5.6%(1/18) vs 6.3%(1/16) vs 11.1%(2/18)
Asthenia: 12.5%(2/16) vs 5.6%(1/18) vs 12.5%(2/16) vs 11.1%(2/18)
At Least One AE: 75.0%(12/16) vs 83.3%(15/18) vs 93.8%(15/16) vs 83.3%(15/18)
Back Pain: 12.5%(2/16) vs 11.1%(2/18) vs 0.0%(0/16) vs 16.7%(3/18)
Body Pain: 6.3%(1/16) vs 16.7%(3/18) vs 6.3%(1/16) vs 5.6%(1/18)
Diarrhea: 6.3%(1/16) vs 5.6%(1/18) vs 25.0%(4/16) vs 33.3%(6/18)
Dizziness: 6.3%(1/16) vs 16.7%(3/18) vs 31.3%(5/16) vs 5.6%(1/18)
Dry Mouth: 18.8%(3/16) vs 0.0%(0/18) vs 0.0%(0/16) vs 11.1%(2/18)
Dyspepsia: 0.0%(0/16) vs 5.6%(1/18) vs 18.8%(3/16) vs 11.1%(2/18)
Ecchymosis: 12.5%(2/16) vs 0.0%(0/18) vs 12.5%(2/16) vs 0.0%(0/18)
Fever: 0.0%(0/16) vs 0.0%(0/18) vs 12.5%(2/16) vs 11.1%(2/18)
Flu Syndrome: 12.5%(2/16) vs 11.1%(2/18) vs 18.8%(3/16) vs 11.1%(2/18)
Headache: 25.0%(4/16) vs 22.2%(4/18) vs 18.8%(3/16) vs 27.8%(5/18)
Insomnia: 12.5%(2/16) vs 11.1%(2/18) vs 25.0%(4/16) vs 11.1%(2/18)
Myalgia: 12.5%(2/16) vs 0.0%(0/18) vs 6.3%(1/16) vs 0.0%(0/18)
Nausea: 12.5%(2/16) vs 0.0%(0/18) vs 31.3%(5/16) vs 5.6%(1/18)
Somnolence: 18.8%(3/16) vs 44.4%(8/18) vs 25.0%(4/16) vs 38.9%(7/18)
Thirst: 18.8%(3/16) vs 0.0%(0/18) vs 0.0%(0/16) vs 11.1%(2/18)
Olanzapine vs Placebo vs Valproate
Vomiting: 5.6%(1/18) vs 12.5%(2/16) vs 0.0%(0/18)
Smelson et al. 1997267

Substance abuse

Risperidone

Location: US

Trial: Not reported

Funding source: Not reported

Design: CCT only

Setting: Single setting

Jadad: 0

Age: Not reported

Sex: 100% Male

Race: Not reported

Screened: NR
Eligible: NR
Entering: NR
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Not reported
Inclusion criteria:
Recently cocaine-withdrawn patients, met DSM-IV criteria for cocaine dependence, admitted to a locked inpatient substance abuse treatment program

Exclusion criteria:
History of opiate, barbiturate, benzodiazepine, marijuana or alcohol dependence, met DSM-IV criteria for a concurrent Axis I disorder, currently taking medication that could affect the central nervous system, history of seizures, cognitive impairment, head trauma, Beck Depression Inventory>16

Interventions:
Control Group
 vs
Risperidone 1-4 mg/days flexible dose for duration not reported

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7 days
Results:
Substance Abuse: Change in Reduction in Use (Self Report) at 4 weeks:
Risperidone vs Placebo - WMD = 4.40 ( -2.68 , 11.48 )
Smelson et al. 2004270

Substance abuse

Risperidone

Location: US

Trial:

Funding source: Government, Industry

Design: RCT only

Setting: Single setting, VA Healthcare System

Jadad: 3

Age: Mean: 41

Sex:

Race: Not reported

Screened: NR
Eligible: NR
Entering: 35
Withdrawn: 3
Lost to follow-up: 0
Analyzed: 32

Method of AE assessment: Reported spontaneously by patient
Inclusion criteria:
Met DSM-IV criteria for cocaine dependence, reported using at least 6g of cocaine in the past month, responded to cue-exposure with increased craving

Exclusion criteria:
Met DSM-IV criteria for an additional Axis I disorder, history of alcohol, opiate, barbiturate, benzodiazapine or marijuana dependence, taking medication that could affect central nervous system, history of seizures

Interventions:
Placebo for 2 weeks
 vs
Risperidone 1-2 mg/days flexible dose for 2 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7, 14 days
Results:
Substance Abuse: Insufficient data to calculate an effect size

Withdrawals:
Placebo vs Risperidone
Withdrawals:12.5%(2/16) vs 5.3%(1/19)
Withdrawals Due To Adverse Events:0.0%(0/16) vs 5.3%(1/19)
Stoops et al. 2007262

Substance abuse

Aripiprazole

Location: US

Trial: Not reported

Funding source: Government

Design: CCT only

Setting: Single setting

Jadad: 2

Age: Not reported

Sex: Mixed

Race: Caucasian, African Ancestry

Screened: NR
Eligible: 8
Entering: NR
Withdrawn: 0
Lost to follow-up: 0
Analyzed: NR

Method of AE assessment: Monitored
Inclusion criteria:
Current crack cocaine users

Exclusion criteria:
Not for any other current psychiatric diagnosis

Interventions:
Placebo for 7 days
 vs
Aripiprazole 10 mg/days fixed single dose for 7 days

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 7 days
Results:
Substance Abuse: Insufficient data to calculate an effect size
Tiihonen et al.2007271

Substance abuse

Aripiprazole

Location: Western Europe

Trial: Not reported

Funding source: Government, Hospital

Design: RCT only

Setting: Not reported

Jadad: 1

Age: Mean: 36

Sex: Mixed

Race: Caucasian

Screened: NR
Eligible: NR
Entering: 53
Withdrawn: 2
Lost to follow-up: NR
Analyzed: 17

Method of AE assessment: Not reported
Inclusion criteria:
Aged 18 - 65, amphetamine/methamphetamine dependence recent and accustomed intravenous amphetamine / methamphetamine use.

Exclusion criteria:
Not reported

Interventions:
Placebo for 20 weeks
 vs
Aripiprazole 15 mg/days fixed single dose for 20 weeks
 vs
Other, Methylphenidate 18-54 mg/days fixed titration schedule for 20 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 140 days
Results:
Substance Abuse: Change in Proportion of amphetamine-positive urine screens at 20 weeks:
Methylphenidate vs Placebo - RR = 2.25 ( 0.85 , 5.92 )

Substance Abuse: Change in Proportion of amphetamine-positive urine screens at 20 weeks:
Aripiprazole vs Placebo - RR = 0.11 ( 0.01 , 1.92 )

Adverse Events:
Placebo vs Aripiprazole vs Methylphenidate
Transient Ischemic Attack (Attributed To Continued Amphetamine Use): 0.0%(0/17) vs 5.3%(1/19) vs 0.0%(0/17)

Withdrawals:
Aripiprazole
Withdrawals:10.5%(2/19)
Placebo vs Aripiprazole vs Methylphenidate
Ransient Increase Of Liver Enzymes (Attributed To Recently Started HIV Medications) And Withdrawn:0.0%(0/17) vs 5.3%(1/19) vs 0.0%(0/17)
Withdrawals Due To Adverse Events:0.0%(0/17) vs 10.5%(2/19) vs 0.0%(0/17)
Voronin et al. 2008253

Substance abuse

Aripiprazole

Location: US

Trial: Not reported

Funding source: University

Design: RCT only

Setting: Not reported

Jadad: 4

Age: Mean: 27

Sex: 80-99% Male

Race: Caucasian, African Ancestry, Native American

Screened: NR
Eligible: NR
Entering: 30
Withdrawn: 0
Lost to follow-up: 0
Analyzed: 30

Method of AE assessment: Elicited by investigator
Inclusion criteria:
Aged 21-65, alcohol dependence, non treatment seeking.

Exclusion criteria:
Current DSM-IV criteria for drug dependence except nicotine, other major DSM-IV Axis I disorders, psychoactive medication or substance abuse (except marijuana), past history of alcohol-related medical illness, liver enzymes >= 2.5 times above normal, or significant health problems.

Interventions:
Placebo for 8 days
 vs
Aripiprazole 5-15 mg/days fixed titration schedule for 8 days

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 6, 8 days
Results:
Substance Abuse: Change in Complete Abstinence (Alcohol) at 0 weeks:
Aripiprazole vs Placebo - RR = 1.67 ( 0.48 , 5.76 )

Adverse Events:
Aripiprazole vs Placebo
Constipation (Mild): 20.0%(3/15) vs 0.0%(0/15)
Constipation (Moderate): 6.7%(1/15) vs 0.0%(0/15)
Constipation (Severe): 0.0%(0/15) vs 0.0%(0/15)
Day Time Sleepiness (Mild): 33.3%(5/15) vs 73.3%(11/15)
Day Time Sleepiness (Moderate): 40.0%(6/15) vs 13.3%(2/15)
Day Time Sleepiness (Severe): 26.7%(4/15) vs 0.0%(0/15)
Feeling Depressed (Mild): 0.0%(0/15) vs 13.3%(2/15)
Feeling Depressed (Moderate): 0.0%(0/15) vs 6.7%(1/15)
Feeling Depressed (Severe): 0.0%(0/15) vs 0.0%(0/15)
Nervousness (Mild): 40.0%(6/15) vs 0.0%(0/15)
Nervousness (Moderate): 6.7%(1/15) vs 13.3%(2/15)
Nervousness (Severe): 0.0%(0/15) vs 0.0%(0/15)
Trouble Sleeping (Mild): 33.3%(5/15) vs 40.0%(6/15)
Trouble Sleeping (Moderate): 46.7%(7/15) vs 0.0%(0/15)
Trouble Sleeping (Severe): 6.7%(1/15) vs 6.7%(1/15)

Withdrawals:
Aripiprazole vs Placebo
Withdrawals:0.0%(0/15) vs 0.0%(0/15)
Withdrawals Due To Adverse Events:0.0%(0/15) vs 0.0%(0/15)
Hutchison et al. 2001258

Substance abuse

Olanzapine

Location: US

Trial: Not reported

Funding source: Government

Design: RCT only

Setting: Not reported

Jadad: 3

Age: Mean: 23

Sex: Mixed

Race: Not reported

Screened: NR
Eligible: 26
Entering: 26
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Not reported
Inclusion criteria:
Reported drinking >=2 times/week, >= 3 drinks / occasion (2 for women), age >= 21 years old

Exclusion criteria:
Reported ever having received treatment for alcohol problems, have history of cardiac illness, reported hearing loss, were taking medications contraindicated for concurrent use with olanzapine, breath alcohol level >0

Interventions:
Placebo for 2 days
 vs
Olanzapine 5 mg/days fixed single dose for 2 days

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 1, 7 days
Results:
Substance Abuse: Insufficient data to calculate an effect size
Anton et al. 2006254

Substance abuse

Aripiprazole

Location: US

Trial: Not reported

Funding source: Not reported

Design: RCT only

Setting: Multi-center

Jadad: 2

Age: Not reported

Sex: Mixed

Race: Not reported

Screened: NR
Eligible: NR
Entering: NR
Withdrawn: NR
Lost to follow-up: NR
Analyzed: NR

Method of AE assessment: Not reported
Inclusion criteria:
Medically stable, alcohol dependent, outpatients

Exclusion criteria:
Other substance abuse

Interventions:
Placebo for 12 weeks
 vs
Aripiprazole <=30 mg/days frequency not reported for 12 weeks

Run-in/wash-out period:
Not reported

Comorbidities:
None

Timing of outcome assessment: 84 days
Results:
Substance Abuse: Insufficient data to calculate an effect size

AE=Adverse Event, NR=Not Reported

From: Appendix D, Evidence Tables

Cover of Off-Label Use of Atypical Antipsychotics: An Update
Off-Label Use of Atypical Antipsychotics: An Update [Internet].
Comparative Effectiveness Reviews, No. 43.
Maglione M, Maher AR, Hu J, et al.

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