Prevention and Early Intervention Program, London, Ontario, Canada
Prevention and Early Intervention Program, London, Ontario, Canada
Prevention and Early Intervention Program, London, Ontario and Department of Psychiatry, Faculty of Medicine, University of Western Ontario, London, Ontario
Correspondence: Dr Ross M. G. Norman, Room 113B, WMCH Building, 392 South Street, London, Ontario N6A 4G5, Canada. E-mail: rnorman{at}julian.uwo.ca
Declaration of interest None. Funding received from the Medical Research Council of Canada.
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ABSTRACT |
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Aims To test this hypothesis on a sample of 113 patients in a community-based early intervention programme for psychosis.
Method Information was collected concerning a number of possible predictors of cognitive functioning including DUP. These were examined for their relation to performance on an extensive battery of cognitive tests administered shortly after the patients' admission to the programme.
Results Although several variables such as gender, premorbid adjustment, education and handedness predicted cognitive functioning, no relation was found between DUP and performance on any component of the test battery.
Conclusions Findings do not provide support for a toxic effect of DUP on cognitive functioning. Other mechanisms through which DUP might affect outcome such as psychological engulfment, social support and adherence to medication are discussed.
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INTRODUCTION |
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METHOD |
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Untreated psychosis can vary in its course, with some individuals experiencing symptoms continually from onset of the disorder until effective treatment begins, while in other cases the psychosis has a more intermittent course. Hypotheses about the possible toxic effects of psychosis have not specified whether it is the cumulative experience of active psychosis or the time since the initial onset of any psychotic symptoms that is most relevant. The information collected in this study was, therefore, used to estimate both. Onset of treatment was defined as commencement of antipsychotic therapy within PEPP. The period from initial onset of psychosis to treatment is referred to as DUP(onset), and the estimated cumulative period of active psychosis as DUP(active). In addition information was collected by which to estimate duration of untreated illness (DUI), which was defined as the period between the onset of any psychiatric symptoms and initiation of treatment.
Both DUP estimates and DUI were rated for each patient on the basis of all information from structured interviews with patients and relatives (using a modified version of the Interview for the Retrospective Assessment of the Onset of Schizophrenia, Hafner et al, 1992) and review of hospital records. To establish interrater reliability, estimates of DUP as well as DUI were independently assessed by two clinicians (a psychiatrist and a clinical psychologist) on 12 randomly selected patients. The intraclass correlation coefficients for these ratings were all within acceptable limits (0.81 to 0.98). The correlation between DUP(active) and DUP(onset) was 0.87 (P<0.001).
As part of the standard assessment in PEPP, information was collected on the number of years of completed education, judged role of substance use or misuse in precipitating psychosis and history of substance misuse. Handedness was also assessed through questioning and observation of the hand used for tasks such as writing, throwing and using scissors. In addition, a diagnostic interview based on the Structured Clinical Interview for DSM-IV Disorders (First et al, 1997) was carried out and the Premorbid Adjustment Scale (Cannon-Spoor et al, 1982) was completed.
As soon as possible after the participant's entry into PEPP, a battery of cognitive tests was administered by an experienced technician under the supervision of a psychologist. If patients were experiencing acute symptoms of psychosis or disorganised thinking that could interfere with their comprehension of test instructions or their ability to complete the tests, then the assessment was delayed until such symptoms resolved. The mean interval between entry into the programme and the administration of the test battery was 10 weeks (median 7 weeks). Among the instruments used were the following tests.
Wechsler Adult Intelligence Scale and National Adult Reading
Test
The Wechsler Adult Intelligence Scale (WAIS-III) and National Adult Reading
Test (NART) were used to estimate current and premorbid IQ, respectively.
Given that the effects of DUP might be more clearly detectable in indices
reflecting deterioration from premorbid levels of functioning, the NART
(Nelson, 1982) was used as an
index of premorbid verbal, performance and full-scale IQ
(Crawford et al,
1988). Estimates of cognitive deterioration were based on current
full-scale, verbal and performance IQ as assessed by WAIS-III minus the
relevant NART estimates of premorbid IQ.
Wechsler Memory Scale
The Wechsler Memory Scale III (WSM-III) provides a standardised assessment
of several areas of memory function including immediate and delayed auditory
and visual memory and working memory
(Wechsler, 1997).
Paced Auditory Serial Addition Test
The Paced Auditory Serial Addition Test (PASAT) provides a measure of
sustained attention and speed of processing
(Gronwall, 1977). A
tape-recording of 60 randomly arranged numbers between one and nine is played
to the patient, who is required to add the most recently presented number to
the number immediately preceding it and report the answer verbally.
Wisconsin Card Sort Task
The computerised version of the Wisconsin Card Sort Task (WCST) is a
measure of executive function involving abstract concept
formation and ability to shift and maintain set
(Berg, 1948). The most
frequently used indices of performance on the WCST are the number of
categories completed and percentage of perseverative errors.
Stroop Colour and Word Test
In the Stroop Colour and Word Test respondents have to use selective
attention and inhibition to identify the ink colour in which the words
red, green and blue are printed. The
score was calculated as the total number of correct responses in a 90-second
period (Golden, 1978).
Trail-making Test
The Trail-making Test (TMT) is a measure of visuomotor coordination in
which subjects must connect circles in one form (A) on the basis of a simple
rule of consecutive numbers and in the second form (B) by alternating between
numerical and alphabetical sequences. For both forms, A and B, time for
completion was used as the primary index of performance
(Reitan, 1958).
Thurstone Word Fluency Test
The Thurstone Word Fluency Test assesses written verbal fluency
(Thurstone & Thurstone,
1962). Subjects are asked to list as many four-letter words as
possible in 5 minutes beginning with the letter S and in 4 minutes beginning
with the letter C. Oral verbal fluency was assessed through a semantic naming
test in which subjects were asked to name as many animals as possible within 1
minute.
Continuous Performance Test
The Continuous Performance Test (CPT) assesses the capacity for sustained
attention. The particular version of the CPT used was the identical pairs
using numbers (Cornblatt & Keilp,
1994). The primary index of performance is d',
which reflects the discrimination of a signal from background noise.
Prospective Memory Screening
Prospective memory (remembering to carry out actions) is an aspect of
memory functioning that is important in everyday life and is not explicitly
included in the Wechsler Memory Scales
(Dalla Barba, 1993). The
self-report memory questionnaire included in the Prospective Memory Screening
(PROMS) includes an assessment of prospective memory
(Sohlberg et al,
1985). The PROMS was introduced into the cognitive assessment
battery later than other tests and, therefore, results using this test are
based on a reduced sample of 54 patients.
Cognitive Failures Questionnaire
The Cognitive Failures Questionnaire (CFQ) was developed to assess
self-reports of everyday slips or errors in cognitive functioning. The CFQ has
demonstrated sensitivity to everyday cognitive errors that are frequently not
revealed in a laboratory setting, and appears to be uncorrelated with measured
intelligence and educational level
(Broadbent et al,
1982).
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RESULTS |
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The single most common diagnosis on entry into PEPP was schizophrenia, with psychosis not otherwise specified (NOS) and schizophreniform psychosis being the next most frequent. The comparatively high rate of psychosis NOS is undoubtedly due to the early stage of the illness at which many of these individuals were being seen. Experience in PEPP suggests that the great majority of individuals diagnosed with schizophreniform disorder or psychosis NOS on entry progress to a diagnosis of schizophrenia or schizoaffective disorder.
Although only about 7% of the patients were diagnosed as having substance-induced psychosis, alcohol and/or drug misuse was judged to have been a significant contribution to onset of psychosis in 23.1% of cases.
The average DUPs and DUI for this sample are within the range reported by other investigators such as Haas et al (1998) and Larsen et al (1996), and each shows a positively skewed distribution. Log transformation of the three estimates resulted in a non-skewed distribution and these transformed variables were used for all analyses relating DUP and/or DUI to other variables.
At the time of cognitive assessment, 16 patients were not receiving any antipsychotic medication, four were receiving haloperidol, three flupenthixol and four were in a double-blind drug trial. All the others were receiving treatment with novel antipsychotic agents (primarily risperidone and olanzapine).
The data showed substantial levels of dispersion on all cognitive indices, and the ranges and standard deviations were comparable to those reported by others (Spreen & Strauss, 1991).
Predictors of cognitive functioning
Before examining the relationship of DUP to cognitive functioning, it
seemed appropriate to examine the possible relationship of cognitive
functioning to several other factors: gender, medication, handedness,
diagnosis, education, substance use and misuse and premorbid adjustment. In
each case, given the number of cognitive variables being examined, the 0.01
level was used for identifying the statistical significance of any
relationship.
Gender
There were gender differences on several of the cognitive indices, each of
which suggested a better level of functioning by men. Men had significantly
higher estimated full-scale, verbal and performance IQ on the WAIS-III
(t=3.70, P < 0.001; t=3.30, P <
0.01; and t=3.27, P < 0.01, respectively). The
differences in mean IQs ranged between 13 and 15 points. Males also showed
significantly superior performance on the information, comprehension, picture
completion, block design, matrix reasoning, object assembly sub-tests and the
verbal comprehension and perceptual organisation indices of the WAIS-III.
Evidence of a discrepancy such that estimated premorbid IQ is greater than
current IQ is often interpreted as reflecting deterioration. Given that there
were no significant gender differences on the estimates of premorbid IQ on the
NART, the WAIS-III differences also resulted in females showing significantly
greater estimated deterioration (using the NART-WAIS-III contrast) in
full-scale, verbal and performance IQ than did males (t=4.28,
P < 0.001; t=4.07, P < 0.001; and
t=3.6, P < 0.001, respectively). Males also showed
significantly fewer perseveration errors on the WCST (t=3.49,
P < 0.01).
Age of onset
Age of onset of psychosis was not found to be correlated with any of the
cognitive indices except TMT B performance wherein later age of onset was
associated with poor performance (r=0.33, P < 0.01).
Medication
Medication being received by the patient at time of cognition assessment
was examined. The only three medication conditions for which there were 10 or
more patients were no medication (n=14), risperidone (n=48)
and olanzapine (n=26). Contrasts were carried out between these three
conditions to assess whether there were significant differences on any of the
cognitive indices. None of the differences in mean performance reached the
0.01 level of significance.
Handedness
Of the 113 participants, 101 were right-handed and 12 were left-handed.
Cognitive indices on which left-handed subjects showed poorer performance than
right-handed subjects were the letter-number sequencing and digit symbol
sub-tests and processing speed index on the WAIS-III, and all indices of
visual and auditory memory (immediate, delayed and general), and the working
memory index on the WMS-III.
Diagnosis
The only cognitive variable to which overall category of diagnosis was
related at the 0.01 level was the matrix reasoning subscale of the WAIS-III,
on which those considered to be suffering from a substance-induced or
medically related psychosis performed substantially better than the other
groups.
Substance misuse
There were no significant differences in cognitive performance between
those for whom substance misuse was an apparent contributor to onset and those
for whom it was not.
Education
Years of education were positively related to verbal, performance and
full-scale WAIS-III IQ (r=0.51, 0.34 and 0.44, respectively, all
P < 0.01) as well as all WAIS-III sub-scores except picture
completion, block design and object assembly. More education was also related
to better performance on the NART (r=0.47, P < 0.001),
Stroop test (r=0.30, P < 0.01), written word fluency test
(r=0.33, P < 0.01), d' on the CPT
(r=0.37, P < 0.001) and the immediate and delayed
auditory memory and working memory indices of the WMS-III (r=0.32,
0.32 and 0.34, respectively, P < 0.01).
Premorbid adjustment
The Premorbid Adjustment Scale (PAS) provides ratings of premorbid
adjustment for childhood (up to age 11 years), early adolescence (ages 12-15
years), late adolescence (16-18 years) and adulthood (19 years and over), as
well as a general assessment of premorbid adjustment prior to onset of
illness. Because of the young age of most of the sample, only premorbid
adjustment in childhood and adolescence was examined as a predictor of
cognitive functioning. Better premorbid adjustment in childhood was associated
with better performance on many of the indices of cognitive functioning
including full-scale, verbal and performance IQ as assessed by the WAIS-III as
well as most of its sub-tests; all WMS-III indices; NART estimated premorbid
IQ; written word fluency; and CPT performance. Better premorbid adjustment
during early or late adolescence was related to fewer cognitive indices at the
0.01 significance level letter-number sequencing and comprehension on
the WAIS-III; WMS-III delayed visual memory, immediate auditory, working
memory and general memory indices; and CPT performance as reflected in
d'.
Relationship of DUP and DUI to cognitive performance
Table 2 reports the
first-order correlations of log transformed DUP(onset), DUP(active) and DUI
with the cognitive performance indices. Only one of the correlations was
significant at the 0.01 level. The one significant result was a correlation of
-0.26 between DUP(active) and the index of deterioration in verbal IQ,
suggesting less deterioration being associated with longer periods of active
untreated psychosis. Six-month or 1-year cut-offs have sometimes been used by
those examining the significance of DUP (e.g.
McGorry et al, 1996;
Haas et al, 1998). When DUP or DUI were dichotomised around either of these cut-offs,
t-tests revealed no significant findings of longer DUPs or DUI being
related to poor cognitive functioning.
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The possibility exists that some relations between DUP and cognitive functioning are being masked by other variables. An important consideration in this context is the extent to which DUP (or DUI) is correlated with any of the above variables that might be expected to influence cognitive functioning. Both DUP(onset) and DUP(active) were found to be significantly correlated with poor premorbid adjustment during early and late adolescence (r values between 0.27 and 0.33, P < 0.01). Furthermore, DUP and DUI were significantly greater for patients who were not receiving antipsychotic medication at the time of cognitive testing (F[1,111]=17.4, 16.3 and 10.2 for DUP(active), DUP(onset) and DUI respectively, all P < 0.01). This is a particularly interesting finding, the possible implications of which we shall return to later.
Partial correlations between log transformed DUP and cognitive indices were calculated removing the variance attributable to years of education, premorbid adjustment, handedness, gender and whether or not the patient was receiving antipsychotic medication. In no case were significant relationships found that would indicate that longer DUPs were associated with poorer cognitive performance.
Bilder et al (1988) suggested that neuropsychological indices are more likely to reflect structural abnormalities in the brain when level of premorbid functioning is controlled. The measures of premorbid functioning used by Bilder et al were age-standardised WAIS sub-test scores for vocabulary and information. Another index likely to reflect premorbid functioning that was included in this study is premorbid IQ as estimated by NART. When partial correlations were calculated controlling for either of these estimates of premorbid functioning, the results did not show evidence of a significant negative correlation between DUPs, DUI and any index of cognitive performance.
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DISCUSSION |
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The estimation of DUP and DUI is challenging, but the methods used in the current study yielded good interrater reliability. Furthermore, the indices of DUP, DUI and cognitive performance showed dispersion comparable to previous reports and so restricted variation does not appear to be a plausible explanation for our negative findings.
There was evidence of a significant negative correlation between DUP, particularly the period of untreated active psychosis, and an index of deterioration in verbal IQ based on the discrepancy between WAIS-III and NART scores. Finding that longer DUP is associated with less evidence of cognitive deterioration is counter to the hypothesis of psychosis having toxic effects, but could reflect the ability of individuals with less deterioration to function for longer periods without treatment.
Consistency with other reports
The only other report of which the authors are aware that examines the
relationship between DUP and cognitive functioning is a paper by Barnes et
al (2000). In a smaller
sample and using a somewhat different cognitive battery, they too found no
relationship of longer DUP or DUI to poorer cognitive function. Should future
studies similarly fail to find relationships between DUP (in particular) and
indices related to brain functioning, it would clearly call into question the
hypothesis that the experience of psychosis, in itself, has a major and at
least partially irreversible influence on brain functioning.
The differences found in cognitive performance as a function of handedness, education and premorbid adjustment parallel those reported by others (Bilder et al, 1992; Albus et al, 1997). The finding that males performed better on several cognitive indices than did females may seem surprising given that women are often reported to have a better response to treatment than men (Castle & Murray, 1991). Nevertheless, there is evidence that past findings of greater cognitive deficits for males are not always replicated and/or may be restricted to chronic patients rather than those early in the course of such illness (Hoff et al, 1998). Our finding of no relationship between age of onset and cognitive impairment is also consistent with recent evidence (Heaton et al, 2001).
Other possible mediators of the effects of DUP
If the experience of longer untreated psychosis does not result in
deterioration of brain functioning, why, then, is there some evidence (e.g.
Loebel et al, 1992;
McGorry et al, 1996)
that patients with shorter DUP may have a better response to treatment, at
least for the first year or two? There are several potential mediators of a
relationship between DUP and response to treatment, including the extent of
psychological engulfment by the illness, and compromised social support (e.g.
Erickson et al, 1989; Aguilar et al, 1997).
Another possibility is that longer DUP is associated with a tendency to less
adherence to an antipsychotic medication regimen. There have been some reports
suggesting that individuals with longer DUP may have had a tendency to take
sporadic or token amounts of medication (e.g.
Haas & Sweeney, 1992;
Larsen et al, 1996).
As noted earlier, there was some association in our study between longer DUP
and decreased likelihood of receiving antipsychotic medication at time of
testing. A review of case notes and discussions with treating clinicians of
such patients in our sample revealed that a common reason for not receiving
medication was reluctance on the part of the patient to take an antipsychotic
drug. It will be important to investigate the possibility that common factors
such as denial, embarrassment and distrust of medical treatment could result
in both prolonged DUP and reluctance to adhere to treatment, and that the
latter may be one mediator of any relation of DUP to treatment outcome.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication November 9, 2000. Revision received March 15, 2001. Accepted for publication March 15, 2001.
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