Background
Objective
Methods
Types of studies
Types of participants
Types of intervention
Types of outcome measures
1. Global outcomes
2. Symptoms of disease
3. Tolerability
4. Concomitant medication
Search strategy for identification of studies
1. Electronic searching
2. Reference searching
Methods of the review
1. Selection of trials
2. Data collection
3. Data synthesis
3.1 Data presentation
3.2 Sensitivity analyses
3.2.1 First episode
3.2.2 Intention to treat analyses
4. Heterogeneity
5. Addressing funding bias
Results
Description of studies
Study | Comparators | Doses (DDD) | Diagnoses | Age | Phase/status | N0/Nitt/N1
| Follow-up | Funding |
---|---|---|---|---|---|---|---|---|
FIRST EPISODE | ||||||||
Crespo-Facorro et al. [24] | Haloperidol Olanzapine Risperidone | 5.4 mg (0.68) 15.3 mg (1.53) 4.0 mg (0.80) | Schizophrenia and related, non-affective psychosis | 15–60 years | Acute, first episode in- and outpatients | 172/172/165 | 6 weeks | Independent |
McEvoy et al. [25] | Olanzapine Quetiapine Risperidone | 11.7 mg (1.17) 506.0 mg (1.27) 2.4 mg (0.5) | Schizophrenia, schizoaffective- schizophreniform disorder | 16–40 years | Acute, first episode in- and outpatients | 400/-/119 | 12 months | AstraZeneca company |
Robinson et al. [26] | Olanzapine Risperidone | 11.8 mg (1.18) 3.9 mg (0.78) | Schizophrenia, schizoaffective- schizophreniform disorder | 16–40 years | Acute, first episode | 120/112/81 | 4 months | Independent |
ACUTE PHASE
| ||||||||
Chrzanowski et al. [27] | Aripiprazole Olanzapine | 22.0 mg (1.47) 14.2 mg (1.42) | Schizophrenia | ≥ 18 years | Acute psychosis/chronic stable in- and outpatients | 214/214/147 | 52 weeks | BMS/Otsuka |
Kraus et al. [28] | Olanzapine Risperidone | 12.4 mg (1.24) 3.4 mg (0.39) | Psychosis; positive symptoms | 18–60 years | Acute, inpatients | 85/-/68 | Not defined | Independent |
McCue et al. [29] | Aripiprazole Haloperidol Olanzapine Quetiapine Risperidone Ziprasidone | 21.8 mg1 (1.45) 16.0 mg 1(2.00) 19.1 mg 1(1.91) 652.5 mg1 (1.63) 5.2 mg1 (1.04) 151.2 mg1 (1.89) | Schizophrenia, schizoaffective- schizophreniform disorder | ≥ 18 years | Acute, inpatients | 327/319/301 | 3 weeks | Independent |
CHRONIC PHASE
| ||||||||
Jerrel [30] | Olanzapine Risperidone Haloperidol Haloperidol (d) Fluphenazine (d) | 13.8 mg (1.38) 5.3 mg (1.06) 15.5 mg (1.93) 6.3 mg (1.92) 3.0 mg (0.43) | Schizophrenia and schizoaffective disorder | 18–54 years | Chronic, inpatients acute care | 108/-/84 | 12 months | Independent |
Lieberman et al. [31] | Olanzapine Perphenazine Quetiapine Risperidone Ziprasidone | 20.1 mg (2.01) 20.8 mg (0.69) 543.4 mg (1.36) 3.9 mg (0.78) 112.8 mg (1.41) | Schizophrenia | 18–65 years | Chronic, not treatment resistant, in- and outpatients | 1493/1432/371 | 18 months | Independent |
Mullen et al. [32] | Quetiapine Risperidone | 329.0 mg (0.82) 5.0 mg (1.00) | Psychotic disorders2
| > 18 years | Outpatients | 728/-/493 | 4 months | AstraZeneca company |
Ritchie et al. [33] | Olanzapine Risperidone | 9.9 mg (0.99) 1.7 mg (0.34) | Schizophrenia | > 60 years | Outpatients, switch from FGAs | 66/61/52 | switch period (mean 40 days) | Eli Lilly company |
Ritchie et al. [34] | Olanzapine Risperidone | 12.4 mg (1.24) 2.0 mg (0.39) | Schizophrenia | > 60 years | Outpatients, switch from FGAs | 66/61/42 | 6 months | Eli Lilly company |
Rosenheck et al. [35] | Olanzapine Perphenazine Quetiapine Risperidone Ziprasidone | Not disclosed - - - - | Schizophrenia | 18–65 years | Chronic, not treatment resistant, in- and outpatients | 1493/1424/363 | 18 months | Independent |
Stroup et al. [36] | Olanzapine Quetiapine Risperidone Ziprasidone | 20.5 mg (2.05) 565.2 mg (1.41) 4.1 mg (0.82) 115.9 mg (1.45) | Schizophrenia | 18–65 years | Chronic, not treatment resistant, in- and outpatients, discontinued previous SGA because of intolerability | 444/333/88 | 18 months | Independent |
Stroup et al. [37] | Olanzapine Quetiapine Risperidone | 20.7 mg (2.07) 586.1 mg (1.47) 3.7 mg (0.74) | Schizophrenia | 18–65 years | Chronic, not treatment resistant, in- and outpatients, discontinued Perphenazine | 115/114/37 | 18 months | Independent |
Swartz et al. [38] | Olanzapine Perphenazine Quetiapine Risperidone Ziprasidone | Not disclosed - - - - | Schizophrenia | 18–65 years | Chronic, not treatment resistant, in- and outpatients | 1493/985/455 | 18 months | Independent |
Tunis et al. [39] | Olanzapine Risperidone Haloperidol Perphenazine | 13.5 mg (1.35) 4.9 mg (0.99) 11.0 mg (1.37) 14.2 mg (0.47) | Schizophrenia, schizoaffective- schizophreniform disorder, ≥ 18 on the BPRS | ≥ 18 years | Primarily outpatients | 664/-/455 | 12 months | Eli Lilly company |
Global outcomes
Studies | Main results (outcome measures) |
---|---|
FIRST EPISODE | |
Crespo-Facorro et al. [24] | No global outcomes |
McEvoy et al. [25] |
O = Q = R (time to discontinuation for any cause, for inadequate therapeutic effect, for unacceptable side effects, for patients decision) |
Robinson et al. [26] |
O = R (rate of discontinued intervention) |
ACUTE PHASE
| |
Chrzanowski et al. [27] | No global outcomes |
Kraus et al. [28] |
O = R (Duration of hospitalisation) |
McCue et al. [29] |
H = O = R > A = Q = Z (no longer needing acute in-patient care)(p < 0.0001)
A = H = O = Q = R = Z (time until treatment classified as effective, i.e. no longer needing acute in-patient care, medication ineffective as judged by discontinuation because of no significant improvement after at least 3 weeks of treatment, side-effects or significant deterioration of patient's mental state.) |
CHRONIC PHASE
| |
Jerrel [30] |
O (p = 0.02) & R (p = 0.005) > FGA (total mental health treatment costs)1
O > R & FGA (odds of compliance) (p < 0.001)
O = R = FGA (psychosocial functioning (RFS), time to discharge and rehospitalisation, client satisfaction (CSQ)). |
Lieberman et al. [31] |
O > Q (p < 0.001) & R (p = 0.002) (Time to discontinuation for any cause)
O > P (p < 0,001) = Q (p < 0.001) = R (p < 0.001) (Time to discontinuation for lack of efficacy)
O = Q = P = R = Z (Time to discontinuation for intolerable side effects)
O > Q (p < 0.001) = R (p = 0.008) (time to discontinuation due to patient's decision)
Q > Z > P > R > O (p < 0.001) (hospitalisation for exacerbation of schizophrenia) |
Mullen et al. [32] | No global outcomes |
Ritchie et al. [33] |
O = R (quality of life, except O > R for psychological well-being (p = 0.02) |
Ritchie et al. [34] |
O > R (physical health (p = 0.03), social relationships (p = 0.015); overall quality of life (p = 0.04), health satisfaction (p = 0.03))
O = R (psychological well-being, environmental domain) |
Rosenheck et al. [35] |
O = Q = R = Z > P (total health care costs) (p < 0.001)
O & Q & R & Z > P (total medication costs) (p < 0.0001)
O > Q & R & Z (drug costs) (p = ?)
P > R (Quality Adjusted Life Years ratings) (p < 0.005)
O = P = Q = R = Z (quality of life measures) |
Stroup et al. [36] |
O = R > Q (p < 0.05) = Z (p < 0.01) (time to discontinuation for any cause)
O = Q = R = Z (time to discontinuation for lack of efficacy/for intolerable side effects)
O > Q = Z (time to discontinuation for patients who previously discontinued SGA due to inefficacy) (p < 0.01)
R > Q (time to discontinuation for patients who previously discontinued SGA due to inefficacy) (p < 0.05)
Q > Z > R > O (p = 0.02) (hospitalisation for exacerbation of schizophrenia) |
Stroup et al. [37] |
O (p = 0.02) = Q (p = 0.04) > R (Time to discontinuation for all causes)
O = Q = R (cause of discontinuation) |
Swartz et al. [38] |
O = P = Q = R = Z (change in the Quality of life total and subscores at 6, 12 and 18 months) |
Tunis et al. [39] |
O = R = FGAs (total costs)
O > R & FGA (antipsychotic costs) (p < 0.001)
R (p < 0.001) > FGA (p < 0.001) > O(rate of switching from assigned antipsychotic agent)
O > R (p = 0.002) & FGA (p = 0.043) (mean social responder days
2) |
Symptoms of disease
Studies | Main results (rating scales/outcome measures) |
---|---|
FIRST EPISODE | |
Crespo-Facorro et al. [24] |
O = R = H (CGI-S, BPRS, SAPS, SANS, HAM-D, CDS, YMRS, response
1
rate, mean time to response) |
McEvoy et al. [25] |
O = Q = R (PANSS total change)
O > Q (PANSS positive subscale reduction) (p = 0.013)
O = Q = R (response rate
2) |
Robinson et al. [26] |
O = R (cumulative response
3
rates, mean time to response)
O = R (delusions, hallusinations, thought disorders (SADS-C+PD positive symptoms items); affective flattening, alogia, avolition-apathy, asociality-anhedonia (SANS))
R > O (mean length of time that subjects maintained the of responder status) (CI= 8.6-10.4 vs. 5.6-7.7) |
ACUTE PHASE
| |
Chrzanowski et al. [27] |
A = O (PANSS, CGI-I) |
Kraus et al. [28] | No outcomes |
McCue et al. [29] |
A = H = O = Q = R = Z (BPRS change) |
CHRONIC PHASE
| |
Jerrel [30] |
O = R = FGA (PANSS, BPRS, DIS-III-R Depression and Mania symptoms) |
Lieberman et al. [31] |
O = P = Q = R = Z (PANSS, CGI)
O > Q (p < 0.001) & R (p = 0.002) & P (p = 0.013) (duration of successful treatment
4
)
R > Q (duration of successful treatment) (p = 002) |
Mullen et al. [32] |
Q = R (PANSS)
Q > R (HAM-D) (p = 0.028)
Q = R (CGI-I) |
Ritchie et al. [33] |
O = R (BPRS, SANS, MADRS, MMSE) |
Ritchie et al. [34] |
O = R (BPRS, SANS, MADRS, MMSE) |
Rosenheck et al. [35] |
O = P = Q = R = Z (PANSS) |
Stroup et al. [36] |
O > Q (p = 0.005) & Z (p = 0.005) (PANSS)
O > Q (p < 0.001) & Z (p < 0.001) & R (p < 0.02) (PANSS positive symptoms)
R > Z (p < 0.03) (PANSS positive symptoms)
O = Q = R = Z (CGI) |
Stroup et al. [37] |
O = Q = R (PANSS)
O = Q = R (CGI at endpoint) |
Swartz et al. [38] | No outcomes |
Tunis et al. [39] |
O > FGA (mean clinical responder days
5
) (p = 0.025) |
Tolerability
Studies | Main results |
---|---|
FIRST EPISODE | |
Crespo-Facorro et al. [24] |
O = H = R (AIMS)
O = H = R (asthenia, tremor, increased/reduced salivation, erectile and ejaculatory dysfunction, amenorrhoea (UKU))
H > O & R (treatment emergent parkinsonism (SAS) (p < 0.001) and akathisia (BARS) (p < 0.001))
H > O > R (concentration difficulties (p = 0.044), sleepiness/sedation (0.012) increased duration of sleep (p = 0.033) (UKU))
H > R > O (rigidity (p = 0.005), hypokinesia (p = 0.006), akathisia (p = 0.029) (UKU))
O > R > H (weight gain) (p < 0.001) (UKU) |
McEvoy et al. [25] |
O = Q = R (SAS, BARS, AIMS)
O > Q & R(weight gain and BMI change, and male weight gain and BMI change) (p < 0.01)
O > Q (female weight gain and BMI change) (p < 0.001)
R > Q (female weight gain and BMI change) (p < 0.01)
Q & R < O (weight gain > 7 %) (p < 0.05)
O > Q (male weight gain > 7 % (week 12 only)) (p < 0.01)
O > R (male weight gain > 7 %) (p < 0.05)
O > Q (female weight gain > 7% (week 12 only)) (p < 0.01)
R > Q (female weight gain > 7 % (week 52 only)) (p < 0.05)
O > Q (BMI increase ≥ 1 unit) (p < 0.05)
O > R (BMI increase ≥ 1 unit (week 12 only)) (p < 0.01)
O > Q (male BMI increase ≥ 1 unit (week 12 only)) (p < 0.05)
O > R (male BMI increase ≥ 1 unit) (p < 0.05)
O > Q (female BMI increase ≥ 1 unit (week 12 only)) (p < 0.01)
O > R (female BMI increase ≥ 1 unit (week 12 only)) (p < 0.05)
O > R (female waist circumference > 35 inches change (week 12 only)) (p < 0.05)
O & Q > R ((fasting TG levels change (week 52 only) (p < 0.05)
Q > R (increase of proportion with fasting TG level > 150 mg/dl) (p < 0.01)
Q > O (increase of proportion with fasting TG level > 150 mg/dl (week 12 only)) (p < 0.05)
Q > R (fasting total cholesterol change (week 52 only)) (p < 0.05)
O > Q (negative fasting HDL cholesterol change and male negative fasting HDL cholesterol change (week 52 only)) (p < 0.05)
O > R (negative fasting HDL cholesterol change) (p < 0.05)
O > R (male negative fasting HDL cholesterol change (week 52 only)) (p < 0.05)
R > O & Q (prolactin level change) (p < 0.001)
Q > R (systolic blood pressure increase) (p < 0.01)
O > R (systolic blood pressure increase) (p < 0.05)
O > R (diastolic blood pressure increase (week 52 only)) (p < 0.05)
O > R (increase of proportion with systolic blood pressure ≥ 130 mm Hg (week 52 only)) (p < 0.05)
Q > R (increase of proportion with diastolic blood pressure ≥ 85 mm Hg (week 52 only)) (p < 0.05) |
Robinson et al. [26] |
O = R (SAS, BARS)
O > R (weight gain) (p < 0.01) |
ACUTE PHASE
| |
Chrzanowski et al. [27] |
A = O (insomnia, anxiety, headache, somnolence, infection, nervousness, akathisia, schizophrenic reaction, flu syndrome, CNS stimulation, lightheadedness, tremor, SAS, BARS, AIMS, triglyceride change)
O > A (Weight gain (p < 0.001, Weight gain > 7% (p = 0.008), elevated total (p < 0.01) and LDL cholesterol (p < 0.01), negative influence on HDL cholesterol (p < 0.05), QTc prolongation (p = 0.008), prolactin elevation (p < 0.001) |
Kraus et al. [28] | No outcomes |
McCue et al. [29] |
A = H = O = Q = R = Z (SAS, BARS, spontaneous reports of adverse events)
A = H = O = Q = R = Z (withdrawals because of side-effects) |
CHRONIC PHASE
| |
Jerrel [30] |
O = R = FGA (DISCUS, SAS, BARS) |
Lieberman et al. [31] |
O = P = Q = R = Z (any moderate or severe adverse effect, suicide attempt or ideation, hypersomnia, sleepiness, decreased sex drive, arousal, ability to reach orgasm, gynecomastia, galactorrhoea, menstrual irregularities, orthostatic faintness, AIMS, BARS, SAS, discontinuation owing to sedation, change from baseline of blood glucose, change in corrected QT interval, new cataracts)
O > Q > R > P > Z (weight gain > 7%, mean cholesterol and -triglyceride change) (p < 0.001); (meanHbA1c change) (p = 0.01)
O > Q > R > Z* > P* (weight change) (p < 0.001)
O > Z > P > R > Q (HbA1c change) (p = 0.01)
O > Q > P > R* > Z* (cholesterol change, triglyceride change) (p < 0.001)
O > Q > Z > R > P (discontinuation owing to weight gain or metabolic effects) (p < 0.001)
O > Q = P = Z > R (discontinuation owing to intolerability) (p = 0.04)
Q > R > O > P > Z (urinary hesitancy, dry mouth, constipation) (p < 0.001)
Z > P > R > Q > O (insomnia) (p < 0.001)
R > O = Z > Q > P (incontinence, nocturi) (p = 0.04)
P > Z > Q = R > O (discontinuation owing to EPS) (p = 0.002)
R > P > >Z > O > Q (mean prolactin change)(p < 0.001)
Q & R > O & Z (prolonged QTc interval) (p < 0.03) |
Mullen et al. [32] |
Q = R (EPS total (EPS checklist), odds of having an EPS event)
R > Q (for odds of EPS of at least moderate severity (p = 0.03), odds of substantial EPS (p < 0.001), requirement of anti- EPS medication during the trial among baseline EPS patients (p < 0.001)
Q > R (somnolence, dry mouth, dizziness, agitation) (p < 0.05) |
Ritchie et al. [33] |
O = R (SAS, AIMS, BARS, specific side effects) |
Ritchie et al. [34] |
O = R (SAS, AIMS, BARS, sedation, hypotension, dizziness, gastrointestinal side effects, libido, anticholinergics symptoms, weight gain) |
Rosenheck et al. [35] | No outcomes |
Stroup et al. [36] |
O = Q = R = Z (hypersomnia, sleepiness, urinary hesitancy/dry mouth/constipation, incontinence/nocturia, AIMS, BARS, SAS, discontinuation because of intolerable extrapyramidal side effects or sedation, weight change over course of treatment, change of blood glucose and HbA1c, change in QTc interval)
O > Q = R > Z (> 7% weight gain) (p = 0.009)
O > Q > R* > Z * (average change in weigh and cholesterol change) (p < 0.001)
O > Q > Z* > R* (mean change in triglycerides) (p < 0.001)
Q > O > R > Z (orthostatic faintness) (p < 0.05);discontinuation because of intolerable weight or metabolic side effects) (p = 0.004)
Q > R > Z > O (skin rash) (p < 0.05)
Q > Z > O > R (any spontaneous report of moderate/severe adverse effect) (p < 0.02))
R > O > Z > Q (adverse events related to sex drive/sexual arousal/sexual orgasm) (p < 0.05)
R > O = Z > Q (gynecomastia/galactorrhoea) (p < 0.04)
R > Z* > O* > Q* (change of prolactin level) (p < 0.001)
Z > R > Q > O (any serious adverse event) (p = 0.01)
Z > R >Q > O (insomnia) (p < 0.001) |
Stroup et al. [37] |
O = Q = R (any moderate, severe or serious adverse event, insomnia, hypersomnia, sleepiness, urinary hesitancy, dry mouth, constipation, decreased sexual drive, sexual arousal, orgasm, incontinence, nocturia, sialorrhoea, orthostatic faintness, skin rash, AIMS, weight gain > 7%, rate of weight gain, change of blood glucose, HbA1c, QTc interval)
O > Q > R (amount of weight gain) (p = 0.005;, (triglyceride change) (p = 0.03)
O > R > Q (total cholesterol change) (p = 0.01)
R > Q* > O* (change of prolactin level) (p < 0.001) |
Swartz et al. [38] | No outcomes |
Tunis et al. [39] |
O = R = FGAS (any serious AE)
O > FGA (probability of not developing EPS over 1 year among those without EPS at baseline) (p = 0.006)
R (p = 0.023) & FGAs (p < 0.0001) > O (time to 7% weight gain)
O > R > FGA (weight gain for patients on initial antipsychotic regimen) (significant1, p = ?) |
Concomitant medication
Studies | Comparators |
---|---|
FIRST EPISODE | |
Crespo-Facorro et al. [24] |
H = O = R (benzodiazepines for anxiety/agitation or EPS; hypnotics)
H > R > O (anticholinergics for EPS) (p < 0.0001) |
McEvoy et al. [25] |
O = Q = R (postbaseline adjunctive medication use for dysphoria/depression, anxiety, insomnia, agitation/excitement)
O > Q (proportion receiving concomitant medications for parkinsonism or akathisia) (p = 0.021) |
Robinson et al. [26] |
O = R (divalproex, sertraline, benztropin, propranolol, lorazepam) |
ACUTE PHASE
| |
Chrzanowski et al. [27] |
A = O (anticholinergics) |
Kraus et al.* [28] |
O = R (benztropine and/or trihexyphenidyl, mood-stabilizers, antidepressants, haloperidol, quetiapine, ziprasidone, perphenazine, lorazepam and/or clonazepam)
R > O (diphenhydramine and/or hydroxyzine) (p = 0.05) |
McCue et al. * [29] |
A = H = O = Q = R = Z (dosages of additional: haloperidol, lorazepam, benzatropine)
A = H = O = Q = R = Z (patients receiving additional: mood stabiliser, antidepressant, anxiolytic)
A > Q > R > Z > H > O (dosage of diphenhydramine) (p = 0.004)
H > R > Q = Z > A = O (patients receiving anticholinergics) (p < 0.0001) |
CHRONIC PHASE
| |
Jerrel * [30] |
O & R > FGA (odds of being prescribed mood-stabilizers or supplemental antipsychotics) (p < 0.001) |
Lieberman et al. [31] |
O = P = Q = R = Z (lithium, anticonvulsants, oral glucose-lowering drugs, insulin, cholestatin drugs)
R > Z > O > P > Q (antidepressants) (p = 0.03)
R = P = Z > O > Q (hypnotics, sedatives) (p = 0.03)
P = Z > Q > R > O (anxiolytics) (p < 0.001)
P > R > Z > O > Q (anticholinergics agents) (p = 0.01) |
Mullen et al.* [32] | Not disclosed |
Ritchie et al. [33] | Not disclosed |
Ritchie et al. [34] | Not disclosed |
Rosenheck et al. [35] | Not disclosed |
Stroup et al. [36] |
O = Q = R = Z (details not disclosed) |
Stroup et al. [37] |
O = Q = R (lithium, anticonvulsants, antidepressants, hypnotic, sedatives, anxiolytics, anticholinergics, oral glucose-lowering drugs and insulin, cholestatin drugs) |
Swartz et al. [38] | Not disclosed |
Tunis et al. [39] | Details not disclosed |