A meta-analysis of profile and time-course of
symptom change in acute schizophrenia treated
with atypical antipsychotics
Megan Sherwood1,2, Allen E. Thornton3and William G. Honer1
1Centre for Complex Disorders, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
2Department of Psychiatry, St. Paul’s Hospital, Vancouver, BC, Canada
3Department of Psychology, Simon Fraser University, Burnaby, BC, Canada
The profile and time-course of symptom response in acute schizophrenia is unclear. For the present study,
we hypothesized that the time-course would be nonlinear. A meta-analysis was performed using ran-
domized, controlled clinical trials of five atypical antipsychotics reported in nine electronic databases.
Studies were of subjects experiencing an acute exacerbation of illness, with multiple BPRS or PANSS data-
points as outcome measures. A mixed factorial repeated-measures ANOVA was used. Twenty-one pub-
lished clinical trials were identified. Reduction in total symptoms from baseline to 4 wk was associated
with a linear decline in symptomatology (F=23.4, d.f.=1, 7, p=0.002) without attenuation of effect. In
contrast, from baseline to 6 wk the linear symptom reduction (F=76.5, d.f.=1, 12, p<0.001) eventually
flattened at the end of the trial (F=87.2, d.f.=1, 12, p<0.001). Secondary analyses showed a similar pattern
for typical antipsychotics, and the same profile for risperidone and olanzapine as for atypical agents as a
whole. Inclusion of LOCF data altered the results at 4 wk, but not 6 wk; completion rates had no effect on
results. In conclusion, this meta-analysis confirms our hypothesis for 6-wk data. The profile of symptom
change is one of linear symptom reduction until 4 wk, with a flattening of treatment effects by 6 wk.
A curvilinear profile of schizophrenia symptom reduction has possible implications with respect to trial
design and clinical decision-making.
Received 8 January 2005; Reviewed 17 March 2005; Revised 12 June 2005; Accepted 16 June 2005;
First published online 5 September 2005
Key words: Adult, antipsychotic agents, clinical trials, mental disorders, meta-analysis, psychiatric status
rating scales, psychotic disorders, randomized controlled trials, schizophrenia.
Long-standing conventional wisdom holds that while
the side-effects of antipsychotic drugs may be appar-
ent even after the first dose, the response of symptoms
to treatment may take weeks (Barbaran, 2000; Gelder
et al., 2001; Marder, 2000; Miyamato et al., 2003). This
belief has considerable implications for research and
practice. To a great extent, clinical research in psy-
chotic disorders has begun to include a longitudinal
component, designed to address the dynamics of
illness progression or recovery (Breier et al., 1991;
Carone et al., 1991; Fenton and McGlashan, 1991;
Heinrichs and Awad, 1993). Accurate timing of
sampling is important for such studies. Similarly, the
timing of measures of response in clinical trials
depends on the profile of treatment response over
time. Increasingly sophisticated analyses are being
applied to clinical trial outcome data; however, the
validity of models of treatment response over time is
uncertain (Gueorguieva and Krystal, 2004; Lieberman
et al., 2003). In regular clinical practice, knowledge of
the actual time-course of response to antipsychotic
drugs will influence decisions of how long to maintain
patients on an individual drug before considering
changes to treatment (APA, 2004).
Keck et al. (1989) summarized the early literature
tom improvement over time were observed. However,
these studies included heterogeneous diagnoses,
treatment with typical antipsychotics, and use of dis-
similar outcome measures. Only two of these five
studies addressed the time-course over several weeks
Address for correspondence: Dr W. G. Honer, Centre for Complex
Disorders, Vancouver Coastal Health Research Institute, #203-828
West 10th Ave., Vancouver, BC, Canada, V5Z 1L8.
Tel.: 604-875-4827Fax: 604-875-4376
International Journal of Neuropsychopharmacology (2006), 9, 357–366. Copyright f 2005 CINP
for acute schizophrenia. The authors concluded that
the timing and rate of response to treatment remained
uncertain, in part due to the small number of trials
In their recent meta-analysis, Agid et al. (2003)
described an early response to treatment with anti-
sampling 42 studies and over 7000 patients, argues
strongly against a delayed response or non-response
model. Agid et al. sampled broadly, including trials of
medication in both acute exacerbation and chronic
states of illness, as well as subjects treated with typical
and atypical agents by both oral and intramuscular
routes. The authors concluded that antipsychotic
response is greater in the first two weeks compared to
the third and fourth weeks. The approach to analysis
was designed to understand the mechanism of action
of antipsychotic drugs. Questions remain unanswered
concerning responses in acute vs. chronic illness, the
pattern of response beyond 4 wk, and possible biases
introduced by inclusion of studies with only baseline
to end-point values.
The profile and time-course of response for acute
schizophrenia remain unclear. An acute worsening
of symptoms in non-treatment-resistant populations
may approximate the first-episode population, which
is of particular interest to researchers and clinicians
(Lieberman et al., 2003). For the present analysis,
we hypothesized that the time-course of treatment
response to atypical antipsychotic medication would
be nonlinear, with different results at 4 and 6 wk.
We expected continued improvement after 4 wk,
and compared the shape of the time-response curve
at 4 and 6 wk. Our study criteria were more narrowly
defined to reflect current clinical and research popu-
lations, notably with an acute exacerbation of illness,
treatment with an atypical agent, and with multiple
data-points to capture the shape of the time-response
curve. Although this meta-analysis was not designed
to address the following specific areas of interest,
secondary analyses were added with respect to the
symptom change profile of typical antipsychotics and
the profiles of risperidone and olanzapine.
Electronic searches included MEDLINE on OVID from
1966 to September 2003,
September 2003, CINAHL from 1982 to September
2003, a combination of three databases: Cochrane
Database of Systematic Review (CDSR), ACP Journal
EMBASE from 1980 to
Club (ACP), Database of Abstracts of Review of
Effectiveness (DARE) from September 2003, Cochrane
Central Register of Controlled Trials from September
2003, PsychINFO 1974 to September 2003, and LILACS
on line (www.bireme.br/bvs/l/ibd.htm) to December
For the MEDLINE search, key words and phrases used
were ‘schizophrenia’, ‘psychiatric status rating scales’
and the atypical antipsychotic drug names ‘risper-
idone’, ‘olanzapine’, ‘quetiapine’, ‘ziprasidone’, and
‘aripiprazole’. Where possible, these key words were
exploded. Results were limited in the searching
process to ‘randomized controlled trial’, ‘human’,
and ‘English language’. All abstracts were reviewed
from each search, and methods and results from the
References from included and excluded studies from
the Cochrane schizophrenia group systematic reviews
of these five atypical agents were similarly reviewed.
A similar approach was used with the remainder of
the databases, but modifications included ‘rating
scales’ in place of ‘psychiatric status rating scales’,
randomized control trials was used as a key word,
or clinical trials was used as a limit and results were
searched by hand for the double-blind, randomized
We selected randomized, controlled clinical trials of
patients with an acute exacerbation of schizophrenia
treated with an atypical antipsychotic agent. We
further selected trials that reported at least three
data-points between weeks 0 and 6. Selected studies
reported a Brief Psychiatric Rating Scale (BPRS) total
score or a Positive and Negative Syndrome Scale
(PANSS) total score as an outcome measure; there was
no restriction on publication date or sample size. We
did not search for the placebo arms of clinical trials,
unless these were comparison arms for one of the five
atypical agents. Heterogeneity between trials, includ-
ing older trials of typical antipsychotic agents vs.
placebo, was felt to limit the applicability of including
additional placebo results from trials of typical agents.
The inclusion criteria were:
(1) Subjects were diagnosed with schizophrenia,
(2) Trial medication included risperidone, olanzapine,
quetiapine, ziprasidone, or aripiprazole.
(3) BPRS or PANSS total scores were reported for at
least three data-points between baseline and 6 wk.
(4) Double-blind, randomized control trial.
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