Schizophrenia Bulletin Volume 31, Number 2, April 2005
478
TESTING TWO EFFICACY HYPOTHESES FOR
THE TREATMENT OF NEGATIVE SYMPTOMS
W. T. Carpenter,* R. W. Buchanan, D. C. Javitt,
S. R. Marder, N. R. Schooler, U. Heresco-Levy,
B. Kirkpatrick, R. P. McMahon
Maryland Psychiatric Research Center, University of Maryland
School of Medicine, Baltimore, MD, USA
Background: Enduring forms of negative symptoms are an unmet
therapeutic need in schizophrenia. Based on the hypoglutamatergic
hypothesis and preliminary RCT data from Javitt, Goff, and col-
leagues, we evaluated the efficacy of glycine and d-cycloserine. This
5-site, multicenter study is the largest study to date of these agents.
Method: The design is a RCT with co-administration of experimen-
tal drug or placebo with previously prescribed antipsychotic for 16
weeks in patients who have low to moderate psychosis, EPS, and
depression that remain stable throughout the study. All subjects met
criteria for persistent negative symptoms and are stratified according
to SDS deficit/non-deficit categorization. 171 patients were ran-
domly assigned to placebo or glycine or d-cycloserine. Analysis is
based on a mixed model analysis of variance for repeated measures
with negative symptom change as the primary dependent measure.
Results: The primary analysis for negative symptom effectiveness
revealed slight improvement in each group with d-cycloserine vs
placebo {p=0.90} and glycine vs placebo {p=0.63 } with no differ-
ence in the proportion of >20% responders. There was not a
deficit/non-deficit schizophrenia difference. Baseline and change
during treatment values for glycine did not relate to response. At
week 16, 9 responders on glycine actually had lower blood glycine
levels and less change from baseline than 30 non-responders (t=1.57,
df=34.3, p=0.12). A significant treatment x site interaction resulted
from one site (total n=17) with modest improvement on active drugs
and little placebo response while another site (n=24) had worsening
on active drugs combined with a large placebo response. Conclu-
sions: Efficacy and effectiveness hypotheses for glycine and d-
cycloserine were not supported for negative symptoms. This study
had power=0.80 to detect an effect size of 0.25 s.d. at alpha=0.05. A
small effect, or a small treatment responsive sub-group can not be
excluded. Supported by NIMH RO1 MH59807.
LONG- AND SHORT-TERM EFFECTS OF
ARIPIPRAZOLE TREATMENT ON THE PANSS
EXCITEMENT/HOSTILITY CLUSTER OF
SCHIZOPHRENIA SYMPTOMS
W. H. Carson,* R. Marcus, M. Radhakrishnan, S. Hardy,
T. Iwamoto, D. Kostic
Otsuka America Pharmaceutical Co, Princeton, NJ, USA
This abstract presents an analysis of the effects of aripiprazole on
the excitement and hostility symptoms associated with schizophre-
nia. Changes in the excitement and hostility cluster, derived using
factor analysis of PANSS scores from long- and short-term studies,
were subjected to analysis. Short-term data were pooled from five
short-term, multicenter trials of patients with schizophrenia or
schizoaffective disorder, randomized to either aripiprazole (n=885)
or placebo (n=405). A 52-week study comparing aripiprazole
(n=853) with haloperidol (n=430) in patients with schizophrenia was
used in the long-term data analysis. Short-term study results showed
a significant difference in the excitement and hostility factor score
between the aripiprazole and placebo groups, with a mean increase
(i.e., worsening) of 1.29 points with placebo compared with a mean
International Congress on Schizophrenia Research 2005
18. Therapeutics: Treatment Trials
decrease of 0.94 points with aripiprazole (P<0.001). Analysis of two
fixed-dose studies which included haloperidol arms also showed that
both aripiprazole and haloperidol treatments significantly improved
excitement and hostility scores compared with placebo (aripiprazole,
–1.17; haloperidol, –1.11; placebo, 1.48; P<0.001). Results from the
long-term study showed that at week 8, the excitement and hostility
score had decreased from baseline by 2.56 points with aripiprazole
and 2.43 points with haloperidol treatment. This effect was main-
tained over the 52-week study period. Reduction of the excitement
and hostility symptoms associated with schizophrenia was shown to
be more effective with aripiprazole treatment than placebo and com-
parable to treatment with haloperidol.
COGNITIVE PERFORMANCE IN PATIENTS
WITH SCHIZOPHRENIA AFTER
RIVASTIGMINE TREATMENT
S. Chouinard,* J. Poulin, E. Stip, R. Godbout, P. Lalonde,
J. P. Melun, G. Zahirney, L. Ait Bentaleb, H. Cohen
Centre de Recherche Fernand-Seguin, Hopital Louis-H-
Lafontaine, Montreal, QC, Canada
Objective: Previous studies have shown that the cholinergic system is
implied in cognitive functioning. It also have been suggested that it
might be involved in schizophrenia symptoms. Cholinergic agonists,
including acetylcholinesterase inhibitors like rivastigmine, have been
shown to slow down the cognitive decline in demented patients. The
aim of this study was to evaluate the effects of rivastigmine a
cholinesterase inhibitor on cognitive functions in patients with schiz-
ophrenia. Methods: Twenty patients with schizophrenia (age=30-
8years; M=15, F=5) stabilized with atypical antipsychotics and cog-
nitively impaired participated to a 24-week crossover study. Patients
were randomly assigned to condition 1 (rivastigmine for the first 12
weeks and no cholinergic treatment for the next 12 weeks) or condi-
tion 2 (no cholinergic treatment for the first 12 weeks and rivastig-
mine for the next 12 weeks). Patients had neurocognitive evaluations
performed with Cambridge Neuropsychological Test Automated Bat-
tery (CANTAB) at three times (baseline, after 12 and 24 weeks). Drug
titration was 3mg/day reaching 6mg by the first month and progres-
sively increased to 9mg/day, depending of tolerability. Tasks used
were: Stockings of Cambridge (SOC), Rapid Visual Processing
(RVP), Spatial Working Memory (SWM), Paired Associates Learning
(PAL), and Reaction Time (RT) to evaluate executive functions, sus-
tained attention and visual detection, working memory, explicit mem-
ory and procedural memory respectively. Results: Latin Square analy-
ses on all neurocognitive variables showed no significant difference
after rivastigmine treatment. The results failed to show improvement
in attention, memory, or executive functions. Conclusion: Results sug-
gest that acethylcholinesterase inhibitors as rivastigmine have no spe-
cific effect on cognitive functioning in patients with schizophrenia
stabilized with antipsychotics treatment. No improvement or deteri-
oration was observed after rivastigmine treatment. Our future research
will examine the relationships between cognitive performance, sub-
jective complaints and sleep variables after rivastigmine treatment.
ZIPRASIDONE VS HALOPERIDOL FOR THE
TREATMENT OF AGITATION
L. Citrome,* S. Brook, A. Loebel, F. S. Mandel
Clinical Research and Evaluation Facility, Nathan S Kline
Institute for Psychiatric Research, Orangeburg, NY, USA
The purpose of this study is to compare the efficacy of sequential
IM/oral ziprasidone vs IM/oral haloperidol in the treatment of agi-
Schizophrenia Bulletin Volume 31, Number 2, April 2005
18. Therapeutics: Treatment Trials
tation in patients with an acute psychotic disorder. Our methods
included a post hoc analyses of pooled data from 2 randomized stud-
ies comparing mean reductions in BPRS agitation, activation/aggres-
sion, anxiety/depression, positive, and negative factor scores over
the first 3 and 7 days among patients with an acute psychotic disor-
der. In the first study (a 7-day study of subjects with an acute non-
organic psychosis), 90 patients received <3 days IM ziprasidone,
then oral ziprasidone (80-200 mg/d, mean 90.5 +/- 44.9 mg/d) and
42 patients received IM haloperidol, then oral haloperidol (10-80
mg/d, mean 14.0 +/- 10.1 mg/d). In the second study (a 6-week study
of subjects with an acute exacerbation of schizophrenia or schizoaf-
fective disorder), 417 patients received IM ziprasidone, then oral
ziprasidone (80-160 mg/d, mean 116 +/- 30.4 mg/d) and 133 patients
received IM haloperidol, then oral haloperidol (5-20 mg/d, mean 11.5
+/- 3.6 mg/d). Effect was assessed by Hierarchical Linear Model
analysis - repeated assessments of a BPRS factor over time served as
the dependent variable. The two independent variables were ‘treat-
ment group’ (between subject factor) and ‘time’ (within subject fac-
tor). Interaction between treatment group and time was included in
the model. Our results demonstrated that in the first three days of
treatment ziprasidone was superior to haloperidol on the agitation
(p=0.0013), activation/aggression (p=0.0276), and anxiety/depres-
sion factors (p=0.0256), but no differences were seen on the positive
(p=0.3129) or negative factors (p=0.1235). The differences observed
might be attributable to a slight initial worsening of symptoms for the
subjects receiving haloperidol in one of the two studies from which
the data was drawn. After three days efficacy measures for each of
the two treatments converged and further improvement was likely
due to a time effect. Thus, post hoc analyses indicate possible effi-
cacy advantages of ziprasidone over haloperidol for the treatment of
agitation. Given the tolerability advantages of ziprasidone over
haloperidol, overall effectiveness would be expected to be greater
for ziprasidone. Appropriately designed clinical efficacy trials will
need to be done to confirm these preliminary findings.
THE INVESTIGATOR’S ASSESSMENT
QUESTIONNAIRE (IAQ): A NEW CLINICAL
MEASURE FOR OVERALL TREATMENT
EFFECTIVENESS
P. Corey-Lisle,* J. Han, S. Ray, H. Li, L. Hanssens,
G. L’Italien
Bristol-Myers Squibb, Wallingford, NJ, USA
Success of long-term therapy in schizophrenia is contingent upon
treatment effectiveness. Effectiveness is concerned with several
domains (efficacy, safety, and tolerability) in routine care of patients
in usual settings1. We compared a new instrument measuring over-
all treatment effectiveness, the Investigator’s Assessment Question-
naire (IAQ), to standard clinical assessments. The IAQ was used as
a secondary measure in two identically designed, randomized, open-
label studies of atypical antipsychotic treatment in patients with
schizophrenia or schizoaffective disorder (Total N = 1926). The IAQ
is a validated2 10-item, clinician administered questionnaire evalu-
ating the efficacy, safety, and tolerability of antipsychotic therapy.
Each IAQ item is scored on a 5-point Likert scale, items are summed
for a total score with lower scores indicative of greater overall effec-
tiveness. The mean total IAQ scores were correlated to time-to-dis-
continuation (TTD), Clinical Global Impression-Improvement (CGI-
I), and preference of medication (POM), using the pooled clinical
trial data. Criterion-related validity is suggested by the favorable cor-
relation between mean total IAQ scores and CGI-I (r = 0.75, p <
International Congress on Schizophrenia Research 2005
479
0.0001) and POM (r = 0.69, p < 0.0001); construct validity is demon-
strated by the moderate correlation between the IAQ and TTD (r =
0.40, p < 0.0001). Clinical relevance is demonstrated by the finding
that a 1-unit increase in mean total IAQ score would correspond to a
23% increase in hazard for time-to-discontinuation. These results
provide continued validation of the IAQ as a measure of overall effec-
tiveness. Given the large number of antipsychotic treatments avail-
able, it is important for practitioners to have simple-to-administer,
validated clinical instruments to evaluate comparative overall effec-
tiveness between agents. 1. Jaffe AB, Levine J, 2003. Efficacy and
effectiveness of first- and second-generation antipsychotics in schiz-
ophrenia. J Clin Psychiatry 64(Suppl 17):3-6. 2. Tandon R, DeVel-
lis RF, Han J, Li H, Frangou S, Dursun S for the IAQ Validation Study
Group. Validation of the Investigator’s Assessment Questionnaire, a
new clinical tool for assessing response to antipsychotics in patients
with schizophrenia and schizoaffective disorder. Manuscript under
review.
THE PROBLEM OF LAST OBSERVATION
CARRIED FORWARD IN PSYCHIATRIC
RESEARCH
S. M. Cotton,* H. Yuen
ORYGEN Research Centre, Department of Psychiatry, University
of Melbourne, Parkville, VIC, Australia
Missing data is an unfortunate but foreseeable element of longitudi-
nal psychiatric research. Data may be missing due to numerous fac-
tors that may be either exogenous and/or endogenous to the patient.
One of the most prevalent techniques for dealing with missing data
is last observation carried forward (LOCF). Although LOCF is
straightforward and easy to implement, recent research has indicat-
ed that this technique has serious flaws. The aim of this paper will
be to explain the problems that can occur when using LOCF for
research on first episode psychosis. Of particular interest is the effect
that LOCF can have on study parameters such as mean change
scores, standard error of the mean change scores, and type I error
rates. Data will be sourced from a number of studies on patients with
first episode psychosis. It will be demonstrated that LOCF can lead
to deleterious outcomes including overestimating and underestimat-
ing treatment effects, inflating type I error, and distorting covariance
matrices. Caution is warranted with the use of LOCF in research on
first episode psychosis.
DRUG-SPECIFIC CORRELATES OF RELAPSE
RISK IN SCHIZOPHRENIA: A RETROSPECTIVE
ANALYSIS OF RANDOMIZED, DOUBLE-BLIND
COMPARATOR STUDY OF OLANZAPINE
VERSUS RISPERIDONE
W. Deberdt,* H. Liu-Seifert, J. Csernansky, P. Buckley,
J. Peuskens, S. Kollack-Walker, D. VanBrunt
Eli Lilly and Company, Indianapolis, IN, USA
Purpose: To compare correlates of relapse during olanzapine (OLZ)
and risperidone (RIS) treatment. Methods: In a 28-week study, we
examined correlates or relapse in responders (≥20% improvement
on PANSS at 8 weeks) to 10-20 mg OLZ (n=105) or 4-12 mg RIS
(n=94) through logistic regression. Results: Among responders, more
patients relapsed (≥20% worsening on PANSS and CGI-S ≥3) with
RIS (28.7%) than with OLZ (12.4%). Significant correlate-by-treat-
ment interactions were found with severity and improvement of