Evidence Table 3Randomized controlled trials in patients with first-episode schizophrenia

Author, year
Trial Name
NDurationStudy design
Eligibility criteriaInterventions (drug, dose, duration)Run-in/washout periodAllowed other medications/interventionsAge
Other population characteristics (diagnosis, etc)Number screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedOutcome scalesMethod of outcome assessment and timing of assessmentResultsAdverse eventsEPSComments
Apiquian, 2003
Mexican First-Episode Psychotic Study
426 monthsOpen-label, randomization NR Setting: in-patient and outpatient services of the National Institute of Psychiatry (NIP) in Mexico City.between 18 and 45 yr old and met DSM-IV criteria for schizophrenia, schizoaffective or provisional schizophreniform disorders; if they they were on their first psychiatric admission due to psychosis (with a maximum duration of illness of 5 yr) and had a baseline Positive and Negative Syndrome Scale (PANSS) positive syndrome score greater than 17 points with two items scoring at least 4
Exclusion- had received treatment for a period longer than 1 month with an equivalent dose of 5 mg/d haloperidol, if they had concomitant medical or neurological illness, current substance abuse or a history of substance dependence, history of bipolar disorder; high risk for suicide or were agitated.
risperidone (1 mg/d), olanzapine (5 mg/d) or haloperidol (1 mg/d).NRBiperiden and benzodiazepinesMean age 25.5 yrs
73.8% male
Ethnicity: NR
Schizophrenia (61.9% n=26), schizoaffective disorder (16.7%, n=7) and schizophreniform disorder, provisional (21.4%)NR/NR/3612/NR/30PANSS, CDSS, BAS, AIMSPANSS; CDSS,;AIMS; Barnes akathisia scale at baseline, 3 months and 6 monthsMean scores at endpoint
Haloperidol vs. Risperidone vs. Olanzapine
Total 38 vs. 65.7 vs. 38.5
Positive 7.4 vs. 13.3 vs. 8.4
Negative 11.5 vs. 17.3 vs. 10.8
CDSS 1.6 vs. 4.3 vs. 0.4
NRHaloperidol vs. Risperidone vs. Olanzapine
mean BAS 0 vs. 0.6 vs. 0.4
mean AIMS 0.3 vs. 0 vs. 0.1
Completers analysis, only
Crespo-Facorro, 2006
Crespo-Facorro, 2009
1726 weeksRandomized practical clinical trial (acute phase of PAFIP)
University hospital clinic
15–60 yrs; met DSM-IV criteria for principal diagnosis of schizophreniform disorder, schizophrenia, schizoaffective disorder, brief reactive psychosis, schizotypal personality disorder or psychosis not otherwise specified; habitually living in the catchment area; no prior treatment with antipsychotic medication or, if previously treated, a total lifetime of adequate antipsychotic treatment < 6 weeks; current psychotic symptoms of moderate severity or greater assessed by 1 of the 5 items on the SAPS; referred to PAFIP

Exclusion criteria:
DSM-IV diagnosis of mental retardation; met DSM-IV criteria for drug dependence
haloperidol: 3–9 mg/day
risperidone: 3–6 mg/day
olanzapine: 5–20 mg/day
3–5 days (for the 3 patients wo were receiving antipsychotics at first contact)Lormetazepam and clonazepam permitted for management of agitation, general behavior disturbances, and/or insomnia; if clinically significant EPS occurred, anticholinergic medication (biperiden at dose of up to 8 mg/day) was allowed; antidepressants (sertraline) and mood stabilizers (lithium) permitted if clinically neededMean age: 27.3 yrs
Male: 62.2%
100% Spanish
No previous antipsychotic treatment:
Inpatient: 63.4%
202/182/18210 withdrawn after randomization
172 analyzed
BPRS, SANS; SAPS; CGI-S; HAM-D; Calgary Depression Scale (CDS); YMRS; Scale of the Udvalg for Kliniske Undersogelser (UKU); Simpson-Angus Scale; AIMS; Barnes Akathisia Scale (BAS)BPRS, SANS; SAPS; CGI-S; HAM-D; Calgary Depression Scale (CDS); YMRS

Adverse Events:
Scale of the Udvalg for Kliniske Undersogelser (UKU)

Simpson-Angus Scale; AIMS; Barnes Akathisia Scale (BAS)

BPRS, SAPS, SANS, CGI-S and measurements of side effects: baseline, weekly during first 4 weeks, and 6 week study endpoint

Affective symptoms measured at baseline and 6-week study endpoint
Mean change (SD) from baseline to endpoint (haloperidol vs. olanzapine vs. risperidone)
CGI-S: −2.5 (1.0) vs. −2.2 (1.1) vs. −2.2 (1.0); P=0.266
BPRS: −25.3 (14.1) vs. −24.5 (14.9) vs. −21.6 (12.0); P=0.308
SANS: −1.1 (6.5) vs. −3.5 (6.0) vs. −2.1 (5.3); P=0.137
SAPS: −9.7 (4.9) vs. −9.0 (4.8) vs. −9.6 (4.3); P=0.679
HAM-D: −5.5 (8.4) vs. −8.3 (6.8) vs. −5.8 (7.5); P=0.132
CDS: −0.1 (3.6) vs. −1.2 (3.3) vs. −0.7 (3.0); P=.256
YMRS: −6.4 (4.5) vs. −6.6 (4.9) vs. −5.9 (4.8); P=0.720

Clinical response rate (>/= 40% BPRS total improvement from baseline:
haloperidol: 57.1%
risperidone: 52.5%
olanzapine: 63.6%

Mean time to response (SD):
haloperidol: 4.32 weeks (0.24)
risperidone: 4.85 weeks (0.21)
olanzapine: 4.36 weeks (0.23)

Cognitive changes at one year follow-up for 69 patients
olanzapine vs risperidone
mean (SD)change in SAPS score: −10.70(5.36) vs −11.33(5.01)
mean (SD) change in SANS score: −3.50(8.22) vs −2.41 (7.94)
mean (SD) change in CDSS:−0.70(3.55) vs −0.70(3.55) vs −0.59 (2.88)
Mean change (SD) from baseline to endpoint in EPS severity (haloperidol vs. olanzapine vs. risperidone)
BAS: 0.66 (1.16) vs. 0.13 (0.64) vs. 0.36 (0.91); P=0.012
Simpson Angus Scale: 2.27 (2.62) vs. 0.25 (1.61) vs. 1.31 (2.55); P=0.000
Adverse events reported (risperidone vs. olanzapine vs. haloperidol):
Concentration difficulties: 14.3% vs. 3.6% vs. 3.3%; P=0.044
Asthenia: 42.9% vs. 29.1% vs. 27.9%; P=0.169
Sleepiness/sedation: 46.4% vs. 45.5% vs. 23.0%; P=0.012
Increased duration of sleep: 23.2% vs. 12.7% vs. 6.6%′ P=0.033
Increased salivation: 17.9% vs. 3.6% vs. 14.8%; P=0.055
Reduced salivation: 12.5% vs. 12.7% vs. 4.9%; P=0.270
Weight gain (increase >/=4kg): 8.9% vs. 47.3% vs. 23.0%; P<0.001
Erectile dysfunction: 13.9% vs. 3.0% vs. 7.9%; P=0.244
Ejaculatory dysfunction: 5.6% vs. 0.0% vs. 13.2%; P=0.072
Amenorrhea: 10.0% vs. 0.0% vs. 8.7%′ P=0.549
Prescribed anticholinergics for EPS during treatment (haloperidol vs. risperidone vs. olanzapine): 74.5% vs. 32.8% vs. 3.8%; P<0.0001
Rigidity: 14.3% vs. 0.0% vs. 4.9%; P=0.005
Hypokinesia: 19.6% vs. 1.8% vs. 8.2%; P=0.006
Tremor: 7.1% vs. 3.6% vs. 8.2%; P=0.633
Akathisia: 23.2% vs. 5.5% vs. 14.8%; P=0.029
Emsley, 1999
Australia, Belgium, Canada, France, Germany, Great Britain, Korea, The Netherlands, South Africa, and Sweden
1836 weeksRandomized double blind study15 to 45 years; had a diagnosis of provisional schizophreniform disorder (295.40) or schizophrenia without prior treatment according to DSM-III-R; psychotic symptoms requiring an oral antipsychotic agent; had received a maximum of 3 days of emergency treatment for this disorder;
Exclusion- had clinically relevant neurological, electrocardiographic, or laboratory test abnormalities; pregnant or lactating; women of reproductive age not using adequate contraception; mental illness other than schizophreniform disorder or schizophrenia (according to Axis I of DSM-IH-R); psychoactive substance abuse (DSM-III—R criteria)
risperidone or haloperidol 2–8 mg/day for 6 weeksNRAntiparkinsonian drugs or benzodiazepinesMedian age 24–26 years
Male 67%
62% white
17% oriental
15% black
6% other
Age at onset of first symptoms of psychosis (median)=23.5 years
Primary diagnosis (% patients):
 Provisional schizophreniform disorder=93.5
 Paranoid schizophrenia=4.5
 Undifferentiated schizophrenia=1.5
Disorganized schizophrenia=0.5

Level of functioning (% patients):
NR/NR/NR46/NR/182PANSS, BPRS; Extrapyramidal Symptom Rating ScaleBaseline, weeks 1, 2, 4, 6Clinically improved according to total PANSS scores
Risperidone 63% vs. haloperidol 56% (p = 0.19), and Improved according to total BPRS scores
Risperidone 65% and haloperidol 55% (p = 0.08)
CGI change scale - much or very much improved; Risperidone 71% vs. haloperidol 70%
Haloperidol vs. risperidone
Total AEs 90% vs. 78% p < 0.05
Insomnia 16% vs. 10%
Headache 10% in each group
Agitation 11% vs. 8%
Anxiety 8% in each group
Antiparkinsonian medications required - haloperidol 75% vs. risperidone 50%; p < 0.001
Shift from baseline
Haloperidol vs. risperidone
Questionnaire 5.1 vs. 3.9 p = 0.101
Hypokinesia factor 5.4 vs.4.5 p = 0.273
Hyperkinesia factor 2.4 vs. 1.4 p = 0.007
Parkinsonism total 8.1 vs. 6.1 p = 0.060
Parkinsonism + dystonia 8.6 vs. 6.3 p = 0.060
Parkinsonism + dystonia + dyskinesia 9.0 vs. 6.5 p = 0.046
CGI Parkinsonism severity 2.2 vs. 1.9 p = 0.150
Green, 2004
Sub-analysis of Lieberman 2003: Effects of comorbid substance abuse
26212 weeksSame as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Within-group (olanzapine or haloperidol) RR (95% CI) of response for non-substance abusers compared to substance abusers:
Substance abuse disorder: olanzapine=1.24 (0.98, 1.57), haloperidol=1.01 (0.80, 1.29)
Alcohol use disorder: olanzapine=1.47 (1.21, 1.79), haloperidol=1.10 (0.85, 1.42)
Cannabis use disorder: olanzapine=1.18 (0.92, 1.50), haloperidol=0.99 (0.76, 1.28)

Mean change in PANSS Total Score for substance use vs non-substance use within olanzapine or haloperidol groups (all p-values NS):
Substance abuse vs non-substance abuse: olanzapine=17.37 vs 19.77, haloperidol=15.20 vs 18.43
Alcohol abuse vs non-alcohol abuse: olanzapine=15.27 vs 19.73, haloperidol=14.13 vs 18.09
Cannabis use vs non-cannabis use: olanzapine=15.94 vs 20.16, haloperidol=13.44 vs 18.64
Green, 2006
Companion to Lieberman, 2003: Two-year data
2632 yrsSame as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003Same as Lieberman 2003216 (82%) withdrawn/14 (5%) lost to fu (olanzapine=11% vs haloperidol=3%, p=0.0138)/N analyzed unclear (see comment)Same as Lieberman 2003Same as Lieberman 2003PANSS Total Score: no differences between olanzapine and haloperidol groups at weeks 12, 24, 52 and 104 (data NR, Figure 1 reflects symptom changes over time based on results of a mixed repeated measure model analysis)

MADRS: Lower values for olanzapine vs haloperidol at weeks 12 (p<0.008) and 24 (p<0.045), but not at weeks 52 and 104 (data NR)

% patients remaining on treatment at 2 years: olanzapine=23.4% vs haloperidol=12.1%, p<0.0161
Mean survival time in treatment (days): olanzapine=322.09 vs haloperidol=230.38, p<0.0085

Response rates (% patients): olanzapine=67.18% vs haloperidol=59.85%, p=NS
Remission rates (% patients): olanzapine=57.25% vs haloperidol=43.94%, p<0.036
Time to remission: trend toward shorter time for olanzapine (p=0.12)
Withdrawals due to AE's: olanzapine=7/131 (5%) vs
haloperidol=19/132 (14.4%); p=0.0147 (StatsDirect)
Weight gain (mean kg): olanzapine=10.2 vs haloperidol=4.0, p-value NR
Greater than 7% weight gain (% patients): olanzapine=72% vs haloperidol=42%, p<0.0001
Cholesterol level (mg/dl): olanzapine=140 vs haloperidol=133, p=0.005
Non-fasting glucose level: greater with olanzapine at weeks 12 and 24, but not later (data NR)
Fasting blood glucose: similar in both groups (data NR)
At least 1 abnormal SGOT: olanzapine=54.2% vs haloperidol=22%, p<0.0001
At least 1 abnormal SGPT: olanzapine=63.4% vs haloperidol=28.8%, p<0.0001
At least 1 abnormal prolactin level: olanzapine=49.6% vs haloperidol=67.4%, p<0.0040
Serum prolactin level at endpoint: no between-group differences (data NR)
Simpson-Angus Scale (max value): olanzapine=4.57 vs haloperidol=2.28, p<0.001
Barnes Scale (max value): olanzapine=2.83 vs haloperidol=0.98, p<0.0001
AIMS: no between-groups difference, data NR
Anticholinergic use (% patients): olanzapine=20% vs haloperidol=47%, p<0.0001
It was noted that not all subjects finished all measurements at their final visit before dropping out, so on any given measure there were fewer than 263 with follow-up visits, but no N's were provided for any outcomes.
Kahn, 2009
50 sites in 14 countries data from EUFEST study
49812 monthsOpen study, multicenterfirst episode schizophrenia patients with minimal prior antipsychotic treatmenthaloperidol (1–4 mg/day; n=103), amisulpride (200–800 mg/day; n=104), olanzapine (5–20 mg/day; n=105), quetiapine (200–750 mg/day; n=104), or ziprasidone (40–160 mg/day; n=82)

12 months
NRNRNRNRNR/NR/498243/NR/not clearNRTreatment discontinuation; (re)hospitalization rates, psychopathology, severity of illness, and measures of safety and tolerabilityhaloperidol vs amisulpride vs olanzapine vs quetiapine vs ziprasidone

Treatment discontinuations: 72% vs 40% vs 33% vs 53% vs 45%

Comparisons with haloperidol showed lower risks for discontinuation for amisulpride (HR, 0.36; 95% CI, 0.23 to 0.55), olanzapine (HR, 0.27; 95% CI, 0.17 to 0.42), quetiapine (HR, 0.49; 95% CI, 0.33 to 0.73), and ziprasidone (HR, 0.47; 95% CI, 0.29 to 0.76).
NRNRdata from the European First Epidsode Schizophrenia Trial (EUFEST)
Lieberman, 2003
Zipursky, 2005 (time to weight gain results)
US & Europe
HGDH Research Group
26312 wk data (planned study up to 104 wks)RCT
Outpatients, inpatients and ER patients
Multicenter (14 sites)
Age 16–40 yrs; onset of psychotic symptoms before age 35 yrs; DSM-IV criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder as assessed by using the Structured Clinical Interview for DSM-IV; experienced psychotic symptoms (delusions, hallucinations, thought disorder and grossly bizarre behavior) for 1–60 months; two active psychotic symptoms characterized by at least 2 PANSS psychosis items ≥4 or one psychosis item ≥5; CGI score ≥4; required treatment with antipsychotic drugs on a clinical basis; able to provide informed consent and cooperate with research staff, tests and examinations; use of medically accepted contraception for female patients of childbearing potentialOlanzapine 5–10 mg/day up to wk 6; 5–20 mg/day wk 6–12
Haloperidol 2–6 mg/day up to wk 6; 2–20 mg/day wk 6–12
antipsychotics washout 2–14 days depending on clinical statusMedications for insomnia or agitation (lorazepam, diazepam, chloral hydrate) or antipsychotic side effects (benzatropine, biperiden, propanolol, procyclidine)Mean age 23.8 yrs (SD 4.8)
82% male
53% Caucasian
38% African descent
3% East/Southeast Asian
0.8% West Asian
5% Hispanic
2% Other (% >100 due to rounding)
Duration of previous antipsychotic use: 5.9 wks (SD 10.7)
schizophrenia 59%
schizoaffective disorder 10%
schizophreniform disorder 31%
NR/NR/263104/NR/263PANSS; CGI Severity; Montgomery-Asberg Depression Rating ScaleWeekly physician-assessments wks 1–6, biweekly wks 7–12PANSS mean change, based on observed cases at 12 wks:
Total score: O −20.05 (SD 1.55) v H −14.22 (SD 0.87)
Negative scale score: O −2.95 (SD 0.51) v H −1.21 (SD 0.66)
Positive scale score: O −7.41 (SD 1.64) v H −7.06 (SD 0.83)
General scale score: O −9.85 (SD 1.33) v H −6.24 (SD 0.57)
PANSS mean change, based on least squares mean at 12 wks:
Total score: O −16.23 (SD 4.51) v H −10.67 (SD 4.52)
Negative scale score: O −2.27 (SD 0.45) v H −0.76 (SD 0.43)
Positive scale score: O −6.24 (SD 1.22) v H −5.77 (SD 1.22)
General scale score: O −7.93 (SD 1.72) v H −4.36 (SD 1.73)
PANSS between-group p-values, mixed model analysis v LOCF analysis
Total score: p<0.02 v p=0.58
Negative scale score: p<0.04 v p=0.89
Positive scale score: p=0.50 v p=0.76
General scale score: p<0.003 v p=0.25

CGI Severity Score, mean change based on observed cases at 12 wks: O −1.34 (SD 0.22) v H −1.02 (SD 0.23)
CGI Severity Score, mean change based on least squares means at 12 wks: O −1.01 (SD 0.57) v −0.73 (SD 0.57)
CGI between-group p-values: mixed-model analysis p=0.07; LOCF analysis p=0.46

Montgomery-Asberg Depression Rating Scale Score, mean change based on observed cases at 12 wks: O −2.58 (SD 0.25) v H −1.93 (SD 1.56)
Montgomery-Asberg Depression Rating Scale Score, mean change based on least squares means at 12 wks: O −1.63 (SD 2.84) v H 0.92 (SD 2.84)
Montgomery-Asberg Depression Rating Scale Score between-group p-values: mixed model analysis p<0.02; LOCF analysis p=0.07
Weight change: >7% increase in body weight from baseline: O 76/124 (61.5%) v H 28/124 (22.7%);p<0.001 (percentages taken from text; number of patients calculated based on percentages and n listed in Table 3)

Mean increase in BMI: O 2.39 v H 0.88; p<0.001

Time to clinically-significant weight gain of ≥ 7% (weeks): olanzapine=5 vs haloperidol=28; hazard ratio 5.19, p<0.0001
Parkinsonism: O 29/111 (26.1%) v H 63/115 (54.8%); p<0.001

Akathisia: O 14/118 (11.9%) v H 62/121 (51.2%); p<0.001
Malla, 2004
841 yrCCTDiagnosis of schizophrenia, schizophreniform psychosis, schizoaffective psychosis or psychosis not otherwise specified; no medial or neurological disorder likely to cause psychotic symptoms; treatment with only one antipsychotic (risperidone or olanzapine) during the first year; no previous exposure to antipsychotics; completion of ratings of positive and negative symptoms, motor side effects and a neurocognitive battery close to the time of initiation of antipsychotic treatment and 1 year laterRisperidone: allowed dose 1–6 mg/day; median dose 2.5 mg/day
Olanzapine: allowed dose 5–20 mg/day; median dose 10 mg/day
NRAntidepressants (sertraline, paroxetine, venlafaxine, citalopram and nefazodone) and anti-anxiety medications (lorazepam and clonazepam)Mean age 23.7 yrs (SD 7.4)
63% male
Ethnicity NR (note: these characteristics are based on the 32 pts included in the final analysis)
Mean age at diagnosis: 21.6 yrsNR/NR/8452/NR/32SANSbaseline, 1 year physician assessmentsSANS Positive symptom score:
O baseline: 33.3 (SD 18.2); 1 yr: 2.2 (SD 2.6)
R baseline: 24.7 (SD 6.0); 1 yr: 6.2 (SD 10.3)

SANS Negative symptom score:
O baseline: 29.3 (SD 17.8); 1 yr: 9.6 (SD 6.9)
R baseline: 27.6 (SD 15.8); 1 yr: 12.6 (SD 8.3)
NRNo difference between groups reported in text; no further data providedOf note: the results are only based on those pts who stayed on the drug they were initially assigned to AND who were completers (32/84 pts)

Also, in Table 2 it is not clear if the 1 year results represent the SANS score at 1 year or the mean change from baseline
McEvoy, 2006
Patel 2009
CAFE: Comparison of Atypicals in First Episode of Psychosis
40052 weeksDouble blind RCT16–40 years; DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder; be in the first episode of their psychotic illness and been continuously ill for at least 1 month - 5 years. Patients were excluded if a prior psychotic episode had remitted for 3 months or more or if they had prior antipsychotic drug treatment > 16 cumulative weeks; ≥4 on at least one
Positive and Negative Syndrome
Scale (PANSS; 17) psychosis item and a score ≥4 (moderately ill) on CGI-S; women of childbearing potential had to be using a medically acceptable form of contraception.
Exclusion- did not speak English; had a history of mental retardation; pregnant or nursing; had a serious, unstable medical illness; had a known allergy to one of the study medications; serious risk of suicide; or had participated in an investigational drug trial within 30 days
olanzapine (2.5–20 mg/day)
quetiapine (100–800 mg/day)
risperidone (0.5–4 mg/day)
2 week washoutadjunctive antidepressant or mood stabilizer during the first 8 weeks of treatment was not allowed unless approved by the project medical officer. Anticholinergic medications for acute extrapyramidal side effects were permitted for up to a total of 2 weeks over the course of the trial.Mean age 24.5 years
73% male
51.3% white
43.0% black
5.8% other
Schizophrenia 57.8%
Schizophreniform disorder 28.8%
Schizoaffective disorder 13.5%
Age at onset 23.5 years
NR/NR/400281/0/400PANSS, the CGI, and the Calgary Depression Scale for Schizophrenia; Heinrichs-Carpenter Quality of Life Scale
Clinical response was defined as a score =3 on all PANSS items and =3 on the CGI severity item at any time
Primary endpoint was all cause discontinuation
Baseline, at weekly intervals for the first 6 weeks, every other week for the next 6 weeks, and monthly thereafter.
All clinical and laboratory assessments were obtained at baseline, week 12, and week 52 or when the patient terminated the study before week 52
Overall discontinuation before 52 weeks 70% of patients; 68.4% olanzapine, 70.9% quetiapine, 71.4% risperidone. At 12 weeks mean change from baseline in the PANSS positive subscale scores showed greater reductions for olanzapine (−5.2) and risperidone (−5.1) than for quetiapine (−4.0; quetiapine versus olanzapine, p=0.017; quetiapine versus risperidone, p=0.031)

Trmt response at any point in study olanzapine 64%, quetiapine 58% risperidone 65%

Olanzapine vs risperidone vs quetiapine
Weight gain at 12 weeks LSM (SE) in pounds
15.6 (1.1) vs 8.6 (1.1) vs 7.9 (1.1)
Weight gain =7% from baseline: Olanzapine vs risperidone 59.8% vs 32.5%, p<0.001, vs Quetiapine 29.2% (p<0.0001)
Changes in total PANSS and weight gain: NS at 12 weeks (p=0.936)
Weight gain at 52 weeks in pounds
24.2 (1.9) vs 14.0 (1.9) vs 12.1 (1.8), p<0.001
Weight gain of =7% from baseline: Olanzapine vs risperidone: 80% vs 57.6%, p<0.05, vs quetiapine 50.0%, p<0.01
No statistically significant difference between changes in total PANSS score and changes in weight at 52 weeks (p=0.338)
Olanzapine Quetiapine Risperidone (%)
Weight gain 51.1 40.3 41.4
Increased sleep hours 33.8 41.8 27.1
Insomnia 38.4 29.1 33.8
Menstrual irregularities 31.3 23.8 47.1
Decreased sex drive 27.8 26.1 27.1
Akinesia 24.1 24.6 27.1
Dry mouth 21.8 34.3 15.8
Akathisia 20.3 18.7 22.6
Decreased sexual arousal 21.8 16.4 18.1
Decreased orgasm 16.5 15.7 18.8
Orthostatic faintness 11.3 19.4 12.8
Constipation 8.3 11.9 13.5
Sialorrhea 5.3 6.0 13.5
Skin rash 7.5 5.2 6.8
Gynecomastia 6.8 2.2 9.8
Urinary hesitancy 5.3 5.2 3.0
Incontinence or nocturia 3.8 3.7 3.0
Galactorrhea 2.3 0.0 2.3
According to article “There were no significant differences across treatment” groups
Robinson, 2006 (Companion paper to Lieberman 2003, Green 2004, Perkins 2004)
1124 monthsRandomized, open label, rater blindedCurrent diagnosis of DSMIV schizophrenia, schizophreniform disorder, or schizoaffective disorder; age 16 to 40; < 12 weeks of lifetime antipsychotic medication treatment; current positive symptoms or current negative symptoms; for women, a negative pregnancy test and agreement to use a medically accepted method of birth control

Exclusion- meeting DSM-IV criteria for a current substance induced psychotic disorder, psychotic disorder due to a general medical condition, or mental retardation; medical condition/ treatment known to affect the brain; any medical condition requiring treatment with a medication with psychotropic effects; medical contraindications to treatment with olanzapine or risperidone; significant risk of suicidal or homicidal behavior.
olanzapine (2.5–20 mg/day)
risperidone (1–6 mg/day).
NRBenztropine for extrapyramidal symptoms and lorazepam or propranolol for akathisia.Mean age 23.3 years
Male 70%
“diverse ethnic backgrounds” no specifics reported
Onset of psychotic symptoms=slightly over 2 years

Antipsychotic medication naïve (%patients)=78%

Diagnosis (% patients):
 Schizophreniform disorder=17%
 Schizoaffective disorder=8%
474/120/12023/8/112Response - Substantial improvement a priori as a rating of mild or better on the SADS-C+PD positive symptom items (severity of delusions, severity of hallucinations, impaired understandability, derailment, illogical thinking, and bizarre behavior) plus a CGI rating of much improved or very much improved; substantial improvement be maintained for two consecutive visits.
Parkinsonism was defined as being present if two or more of the Simpson-Angus Rating Scale items were rated 2 or one item was rated 3 or higher. An overall extrapyramidal symptom severity score was calculated as the sum of the Simpson-Angus Rating Scale items.
Baseline and every week for the first 4 weeks, then every 2 weeksResponse rates olanzapine (43.7%, 95% CI=28.8%–58.6%) and risperidone (54.3%, 95% CI=39.9%–68.7%).Weight gain olanzapine 17.3% (95% CI=14.2%–20.5%) vs. risperidone 11.3% (95% CI=8.4%–14.3%)Extrapyramidal symptom severity scores
risperidone 1.4 (95% CI=1.2–1.6) vs. olanzapine 1.2 (95% CI=1.0–1.4)
Parkinsonism risperidone 16.0% (95% CI=5.5%–26.6%) vs olanzapine 8.9% (95% CI=0.3%–17.6%)
Schooler, 2005
5552 yrsDouble blind RCT16–45 year-old Structured Clinical Interview for DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder < 1 year; no more than two psychiatric hospitalizations for psychosis; <12 weeks of cumulative exposure to antipsychotics and required antipsychotic treatment upon enrollment

Exclusions- meeting DSM-IV criteria for another axis I diagnosis, including substance dependence or abuse; needing another nonantipsychotic psychotropic medication at enrollment; having a serious or unstable medical illness.
Risperidone (1 to 8 mg/day) or haloperidol (1 to 8 mg/day)3–7-day drug washout period that was waived for extremely ill patients.Chloral hydrate, zolpidem, or flurazepam for sleep; and lorazepam for agitation.Mean age 25 years
70% male
74% White
13% African-American
3% Hispanic
10% Other
DSM-IV diagnosis (% patients):
 Schizoaffective disorder=7.6
 Schizophreniform disorder=44.0

No previous antipsychotic exposure (% patients)=31.0

Age at onset of first episode=24.0 years
NR/NR/559218/0/528PANSS; CGI Severity; EPS rating scaleAssessments with the Positive and Negative Syndrome Scale, CGI, and Extrapyramidal Symptom Rating Scale weekly during the first 4 weeks of the trial and then every 4 weeks for the next 5 months. Months 6–15, every 2 months and every 3 months thereafter.Risperidone vs. haloperidol change from baseline in PANSS
Total −21.0 vs. −20.6 p = 0.49
Positive −6.6 vs. −7.0 p = 0.13
Negative −4.8 vs. −4.2 p = 0.98
CGI change score 2.69 vs. 2.62 p = 0.45
Weight gain at endpoint risperidone [N=211]: mean=7.5 kg, haloperidol [N=204]: mean=6.5 kg, p=0.26
Suicide ideation risperidone 7.2% (N=20) and no suicides vs. haloperidol 9.4% (N=26) with three completed suicides p = nr
Risperidone vs. haloperidol
Dyskinesia Baseline 1.1% vs 1.4%
Emergent 8.3% vs. 13.4%
Persistent 1.8% vs. 3.3%
Extrapyramidal symptoms
Total 3.72 vs 4.72 p = 0.04
Parkinsonism, dystonia 3.28 vs. 4.14
p = 0.05
Dystonia 0.34 vs. 0.35 p = 0.91
Parkinsonism 3.12 vs. 3.97 p = 0.05
Dyskinesia 0.82 vs. 1.11 p = 0.12
Akathisia 0.61 vs. 1.00 p < 0.0001
Strakowski, 2005 (companion to Lieberman 2003, Green 2004, Perkins 2004)
US & Europe
HGDH Research Group
1951 yrSame as Lieberman et al 2003.Same as Lieberman et al 2003.Haloperidol 2–6 mg/day
Olanzapine 5–20 mg/day with adjustments for both during the first 12 wks of study
Same as Lieberman et al 2003Same as Lieberman et al 2003Mean age 25 yrs (SD 5)
80% male
55% White
35% African-American
10% Other
61% schizophrenia
30% schizophreniform
9% schizoaffective
PANSS total: 81 (SD 15)
PAS total: 0.33 (SD 0.16)
Duration of illness: 65 wks (SD 62)
Duration of previous antipsychotic use: 6 wks (SD 10)
Substance abuse disorder: 8%
Hospitalized at index: 57%
NR/NR/195107/NR/195SF-36Planned physician assessments at baseline and at 3 mos, 6 mos and 1 year. Included patients had baseline and at least one additional assessmentNo significant time-to-treatment group effects; significant improvement over time observed for all patients for most SF-36 variables for both interventions
No further data on treatment groups provided; all other results combined interventions
Perez-Iglesias, 2007

Goes with Crespo-Facorro 2006
14512 weeksOpen label and randomized in outpatient and inpatient population at psychiatric hospitalMen and women 15 to 50 years, living in region, experiencing their first episode of psychosis (DSM-IV codes 295, 297, and 298), and never treated with antipsychotic medication.Haloperidol = 4.2 mg/day, Olanzapine = 12.7 mg/day, Risperidone = 3.6 mg/day for 12 weeksNRLormetazepam and clonazepam permitted for management of agitation, general behavior disturbances, and/or insomnia; if clinically significant EPS occurred, anticholinergic medication (biperiden at dose of up to 8 mg/day) was allowed.Haloperidol vs. Olanzapine vs. risperidone
Age 28.6 yrs vs 28.5 yrs vs 26.9 yrs
% male 62.5 vs 61 vs 59.6
Ethnicity 96% white
Haloperidol vs. Olanzapine vs. Risperidone
% Schizophrenia 70 vs. 53.7 vs. 53.2
Schizophreniform disorder 20 vs. 24.4 vs. 21.3
Weight 68.29 vs. 66.39 vs 65.26
BMI 24.33 vs. 22.92 vs 22.2
193/147/14517/8/128BMI and weight baseline and 12 weeks. Also see Crespo-Facorro 2006Body weight; body mass index; and 12-hours-fasting morning levels of total cholesterol, tri-glycerides, low- density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, glucose, homeostasis model assessment (HOMA) index, and insulin.Haloperidol vs. Olanzapine vs. Risperidone
Weight gain (kg) 3.83 (4.89) vs. 7.46 (5.11) vs 5.58 (4.48) Haloperidol vs. Olanzapine P = 0.004, all other NS
BMI gain 1.36 (1.59) vs. 2.62 (1.78) vs 1.87 (1.47) Haloperidol vs. Olanzapine P = 0.008, all other NS

For other results see Crespo-Facorro 2006
See Crespo-Facorro 2006See Crespo-Facorro 2006Goes with Crespo-Facorro 2006
Saddichha, 2007
666 weeksRCT, inpatient, single centerDrug-naïve patients with a DSM-IV diagnosis of first episode schizophrenia.Haloperidol n=15, 15.6 (2.6) mg
Olanzapine n=29, 17(5) mg
Risperidone n=22. 4.5 (1.2) mg

6 weeks
NRNone that would effect weight or metabolismAge 26.7 yrs
% male 47
Ethnicity NR
Weight 48.3 (10.5)
BMI 19.2
NR/NR/NRNR/NR/66Prevalence of obesityWHO definition for Asians and International Diabetes Federation criteriaOlanzapine vs. Risperidone vs. Haloperidol
Weight gain (kg) 5.1 vs. 4.1 vs. 2.8

Treatment -emergent obesity
WHO 10.3% vs. 9.1% vs. 0
IDF 44.8% vs. 36.4% vs. 0
Saddichha, 2008
Saddichha 2008 “Predictors of antipsychotic…” Saddichha 2008 “Diabetes and Schizophrenia-effect of disease or drug..” India
99 (includes the 66 above)6 weeksRCT, inpatient, single centerDrug-naïve patients with a DSM-IV diagnosis of first episode schizophrenia.35 on Olanzapine (16.5 ± 4.6 mg), 33 on Risperidone (4.4 ± 1.2 mg)
31 on Haloperidol ( 13.4 ± 3.6 mg).

6 weeks
NRNone that would effect weight or metabolismAge 26.0 (5.5) yrs
% male 52.5%
66 (66.7%) paranoid schizophrenia
33 (33.3%) undifferentiated schizophrenia.
NR/NR/11011/NR/99ATP III A and IDF criteriaThe presence of the Metabolic Syndrome was assessed using the ATP III A and IDF criteriaOlanzapine vs. Risperidone vs. Haloperidol
 Mets by ATP IIIA 20.0% vs. 9.1% vs. 0%
Mets by IDF 25.7% vs. 24.2% vs. 3.2%
% of patients with weight gain>7% above baseline: Olanzapine vs Risperidone: 77.1% vs 63.6%, p<0.001

Mean Weight gain at endpoint: Olanzapine: 5.0, Risperidone: 4.2, p<0.001
Increase in Fasting blood sugar at endpoint (mean (SD)): Olanzapine 6.6(12.7), Risperidone: 4.3 (12.5), p=0.01
Increase in Post prandial blood sugar at endpoint: Olanzapine: 21.5 (32.2), Risperidone: 21.0 (23.4), p<0.001

Treatment emergent Diabetes: (WHO definition) Olanzapine vs Risperidone: 11.4% vs 9.1% (ADA definition) 2.9% vs 0%

From: Evidence Tables

Cover of Drug Class Review: Atypical Antipsychotic Drugs
Drug Class Review: Atypical Antipsychotic Drugs: Final Update 3 Report [Internet].
McDonagh M, Peterson K, Carson S, et al.
Portland (OR): Oregon Health & Science University; 2010 Jul.
Copyright © 2010 by Oregon Health & Science University, Portland, Oregon 97239. All rights reserved.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.