The Groton Maze Learning Test. Sensitivity to Medication Related Improvement in Executive Function in Schizophrenia

1
The Groton Maze Learning Test. Sensitivity to
Medication Related Improvement in Executive
Function in Schizophrenia
Paul Maruff, CogState Ltd, Melbourne Australia
Peter J Snyder, Pfizer Global Research and
Development, Groton CT, USA, D Piskulic, Austin
Hospital, Melbourne Australia,
Introduction Animal and human data indicate that
impairment in spatial working memory is central
to the clinical presentation of schizophrenia.
Changes in SWM following treatment with
antipsychotic medications may provide a useful
marker of the therapeutic benefits of that
antipsychotic medication. The Groton Maze
Learning Task (GMLT) is a rapid and repeatable
measure of SWM. It provides summary SWM measures
as well as measures of the component cognitive
processes necessary for optimal performance. We
used the GMLT to determine the nature and
magnitude of SWM impairment in unmedicated
patients with first episode schizophrenia/schizoph
reniform disorder and the extent to which these
impairments can be ameliorated by treatment with
antipsychotic drugs.
Table 1 Demographic characteristics of patients
and controls
Fig 2 Improvement in GMLT efficiency (correct
moves per second) with medication and then short
term stability of performance in schizophrenia.
Absence of practice effect in controls.
Measure Controls FE Schiz (unmed group) FE Schizo (medicated group) FE Schiz (stability study)
N 20 34 22 20
Males 16 26 14 13
Rt handed 18 32 21 19
Age (yrs) 22.1 (3.2) 21.5 (4.5) 22.3 (2.3) 21.4 (2.4)
Educ (yrs) 10 (2.1) 11.9 (3.1) 11.7 (2.4) 11.3 (3.1)
Premorbid IQ 101.3 (10.9) 98.4 (11.2) 97.4 (10.3) 99.2 (11.4)
N receiving antipsychotic medication 20 6 22 20
Median Medication dose (cpz equivalents mg/day) - 37.2 (13.4 -136.7) 89.9 (16.7 590) 97.2 (68.2 -590).
Mean treatment at (days) 1.9 (1.3) 32.6 (3.9) 36.2 (3.2)
Mean days since first assessment 32 (5.8) 31.1 (4.5) 36.9 (3.4)
Mean total BPRS 49.5 (9.5) 44.3 (10.1) 44.1 (10.5)
Mean BPRS positive symptoms 15.5 (5.6) 12.5 (4.8) 12.7 (4.1)
Mean SANS Negative symptoms 70.1 (23.7) 68.6 (21.4) 67.1 (24.3)
Patients First Episode schizphrenia/schizophrenifo
rm disorder 34 patients with first-episode
psychosis were recruited from an Early Psychosis
Intervention Program. Admission criteria for
entry were age at onset between 16 and 30 years
and active psychosis (the presence of at least
one of the following 1) delusions 2)
hallucinations 3) disorder of thinking/speech,
other than simple acceleration or retardation
and 4) disorganized, bizarre, or markedly
inappropriate behavior). Diagnosis of
schizophrenia/schizophreniform disorder was made
using DSM-IV. All patients completed the first
assessment within the first week after admission.
32 patients were assessed within 3 days
(antipsychotic-naive window) and 6 were assessed
within 7days (by which time they had begun taking
medication, (Table 1). Other medication taken by
patients by the first assessment included
benzodiazepines (N5), anticholinergics (N4),
anxiolytics (N15), lithium (N2),
anticonvulsants (N2) or antidepressants (N4).
23 patients were reassessed approx 30days after
treatment began. 20 of these completed a further
2 assessment over the following week. All
re-assessed patients had been receiving atypical
antipsychotic medication with dose and type
chosen by the treating physician (doses shown on
Table 1). Controls A group of healthy age
matched controls was recruited from among
unemployed individuals who were attending a
government work skills training program. These
subjects completed the assessments at baseline,
30days, 32days and 35 days. The research
project was approved by institutional research
and ethics committee and all patients and
controls gave informed consent prior to any study
procedures being conducted. Groton Maze Learning
Test (GMLT) The Groton Maze Learning Test
(GMLT), consists of a 10 x 10 grid of tiles
presented on a computer touchscreen in which
28-step pathway was hidden (Fig 1). The start
(top left) and finish (bottom right) of the
pathway were shown. Subjects were instructed to
move one tile at a time from the start toward the
end while adhering to two rules, 1) do not move
diagonally and 2 ) do move back to any location
already identified. The computer indicated
whether each move was correct (i.e., was the next
step in the pathway) or incorrect. Correct
locations were not marked in any way. If
incorrect, the subject had to touch the last
correct tile and then choose a different tile to
advance toward. After completing the pathway,
the subject repeated the learning process four
more times (n5 trails).
Fig 2 Magnitude of SWM impairment in FE
schizophrenia relative to healthy controls before
and after medication
Fig 1 Example of one GMLT pathway in the 10x10
matrix
Conclusion Impairment in spatial working memory
is large in magnitude in the earliest stages of
the schizophrenia illness. The magnitude of
impairment is reduced with antipsychotic
medication although performance on the GMLT is
still abnormal compared to controls. Qualitative
analysis of the GMLT indicates the poor
performance on the GMLT arose from difficulty
with holding the general rules for performance in
working memory (rule break errors) and from
learning on the basis of experience (legal
errors). The impairment in SWM detected with the
GMLT were stable over a week after medication
indicating the reliability of the test for use in
clinical trials aimed at improving SWM in
medicated schizophrenia
The pathway remains hidden throughout each
learning trial and subjects must locate this on
the basis of trial and error learning while
adhering to two general maze rules (dont go
back, no diagonal moves). On each trial, the
number and type of errors (legal errors, rule
breaks perseverative errors) made as well as the
time (in msecs) was recorded. All subjects
received alternative forms of the test on
repeated assessments.