Division of Psychiatry, University of Edinburgh, UK
Correspondence: Dr Andrew McIntosh, Division of Psychiatry, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.Tel: +44 (0)131 537 6274; fax: +44 (0)131 537 6531; e-mail: andrew.mcintosh{at}ed.ac.uk
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To examine the possibility that these abnormalities may provide a means by which the disorders might be separated and to clarify the associations of phenotypic expression and genetic liability.
Method A neuropsychological test battery was administered to 50 control participants, 74 patients and 76 unaffected relatives recruited for the study.Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both disorders.Unaffected relatives were also recruited.
Results Current, verbal and premorbid IQ were impaired in people with schizophrenia and in their close relatives. Memory was impaired in all patient and relative groups. Psychomotor performance and performance IQ were impaired in patients, regardless of diagnosis.
Conclusions This study finds evidence that intellectual abnormalities are related to a genetic liability to schizophrenia. Abnormalities of memory appear to be related to an increased liability to psychosisin general.No impairment was specific to bipolar disorder.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All people fulfilling study inclusion criteria were interviewed using version 9 of the Present State Examination (PSE; Wing et al, 1974). The PSE was used to supplement the information obtained from case notes, confirm the diagnosis of affected participants and confirm that apparently healthy people were indeed unaffected.
A control group consisting of 50 people with no personal or family history of schizophrenia or affective disorder was also recruited from the social network of the participants. Control status was confirmed using the Schedule for Affective Disorders and Schizophrenia, Lifetime version (SADSL; Endicott & Spitzer, 1978) and using data about previous medical treatment obtained at interview. Unaffected relatives were similarly interviewed to confirm the lifetime absence of major depressive disorder, bipolar disorder or schizophrenia.
Additional demographic and historical information was collected at interview on all participants using a semi-structured questionnaire. All eligible subsample members and controls were interviewed using the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1987), the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960) and the Young Mania Rating Scale (YMRS; Young et al, 1978).
All relatives and controls gave informed consent to their participation. The study protocol and consent procedures were approved by the relevant ethics committees. Sample sizes were chosen on the basis of a power calculation for two independent groups at a significance level of 0.05.
Neuropsychological assessments
All neuropsychological assessments were administered by two investigators
(L.H. and K.F.), masked to diagnosis. The test battery chosen included tests
that had previously been shown to distinguish individuals with schizophrenia
or bipolar disorder from controls and was organised according to domain of
neuropsychological function (see Appendix). Genetic liability to psychosis was
estimated using a continuous measure described elsewhere
(Lawrie et al, 2001), developed originally by Professor Sham of the Institute of Psychiatry, which
assumes a liability threshold model
(Pearson & Lee, 1901) of
genetic disease. Using the estimated prevalence of the disorder and published
heritability estimates, the average genetic liability of someone selected at
random from a population can be calculated. Using this information on average
genetic liabilities combined with family history data, a revised liability
estimate for individuals is given.
Statistical analysis
The distribution of each neuropsychological variable was examined for
normality using a normal probability plot for each group. Where data were not
normally distributed a ladder of transformations was applied, and that
resulting in the greatest approximation to normal distribution was chosen. The
assumption of multivariate normality was checked further using a Mahalanobis
plot. Standardised residuals from the mixed-effects analyses of variance
(ANOVAs) conducted were also examined for normality.
Domains of neuropsychological function (IQ, executive function and psychomotor performance) were compared between groups using a multivariate analysis of covariance (MANCOVA). All tests conducted included psychiatric symptoms and, where appropriate, age as covariates. Tests of executive function and psychomotor performance were conducted, adjusting additionally for Wechsler Abbreviated Scale of Intelligence (WASI) Full-Scale IQ (Wechsler, 1999). All multivariate analyses were conducted using the PROC GLM procedure within the statistical package SAS, version 8.2 (SAS Institute, Cary, North Carolina, USA). Memory, having only one measure, the Extended Rivermead Behavioural Memory Test (ERBMT; de Wall et al, 1994), was compared between groups using mixed-effects ANOVA.
Where the MANOVA showed an overall difference within a domain of neuropsychological function, further tests were conducted to examine first, which specific neuropsychological variable means differed between the groups, and second, specific pairwise effect sizes. Both analyses were conducted using a mixed-model ANOVA, with family modelled as a random factor to take account of the correlation within pedigrees. Where differences were found in the overall ANOVA, controlling for WASI Full-Scale IQ (for memory and executive function) and psychiatric symptoms (HRSD, PANSS positive sub-scale and YMRS scores), the pairwise between-group contrasts were estimated, controlling for the comparison-wise error rate. Age was also included as a potential confound where this was not adjusted for in the calculation of individual test scores. All analyses were conducted using the PROC MIXED procedure within SAS.
The influence of medication and alcohol consumption were checked by plotting the unstandardised residuals (unexplained variation) from each analysis against current conventional antipsychotic dosage (in chlorpromazine equivalents), lithium dosage and estimated weekly alcohol consumption.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
The patient groups were closely balanced in terms of duration of illness (estimated from current age minus age at first presentation), but differed in terms of psychiatric symptom measurements and prescribed medication (Table 2). Patients with schizophrenia were prescribed more antipsychotic medication and had higher levels of (positive) psychotic and depressive symptoms than patients with bipolar disorder from either bipolar or mixed families. In contrast, patients with bipolar disorder from bipolar families had the highest doses of lithium prescribed and patients with bipolar disorder from mixed families had the highest numbers of manic symptoms compared with the other groups.
|
Neuropsychology
The vectors of intellectual function (F(20,203)=2.02,
P<0.01) and psychomotor function
(F(15,166)=2.0, P=0.02) differed significantly
between the groups using MANCOVA. Executive function showed no evidence of
variation between the groups overall (F(20,196.6)=1.29,
P=0.19). Since the numbers in each group were not sufficiently large
to allow the conclusion that the groups were equal in terms of executive
function, further mixed-effects ANOVAs were conducted to explore whether any
single measure of executive function differed between the groups, despite the
absence of a statistically significant difference overall. The means and
standard deviations of test performance scores are shown in
Table 3; these are raw scores
unadjusted for confounders and for the effects of intrafamilial
clustering.
|
General intellectual function
Premorbid intellectual function, measured using the National Adult Reading
Test (NART; Nelson, 1982), and
current intellectual function measured by WASI Full-Scale IQ, Performance IQ
and Verbal IQ scores (Wechsler,
1999) all differed significantly between the groups. Patients with
schizophrenia and unaffected participants from families with schizophrenia had
significantly lower NART IQ scores than the control group, and patients with
schizophrenia also had significantly lower scores on this measure compared
with people with bipolar disorder from either group. Patients with bipolar
disorder from families with bipolar disorder had significantly higher NART
scores than their unaffected relatives
(Table 4).
|
Patients with schizophrenia, patients with bipolar disorder from
mixed families and unaffected relatives from
schizophrenia families had significantly lower WASI Full-Scale
IQ scores than the control group. Although unaffected relatives from
mixed families did not differ significantly from controls in
terms of WASI Full-Scale IQ, the difference was similar to that found between
unaffected relatives from schizophrenia families and controls (7
IQ points . 10). Patients with schizophrenia also had significantly lower
WASI Full-Scale IQ scores than patients with bipolar disorder from either
group and indeed than their own healthy relatives.
In terms of Verbal IQ, patients with schizophrenia and their healthy relatives had significantly lower WASI scores than controls, but both bipolar disorder groups and their unaffected relatives did not differ significantly from controls. A greater difference was observed between unaffected relatives from mixed families and controls than between unaffected relatives from bipolar families and controls. Patients with schizophrenia also had significantly lower WASI Verbal IQ scores than either their own relatives (difference 9.8, 95% CI 17.45 to 1.83) or either group of patients with bipolar disorder. The latter two groups did not differ significantly from their unaffected relatives on this measure.
The pattern of impairment in terms of WASI Performance IQ differed from that of other intellectual measures. Patients with schizophrenia or bipolar disorder (whether from bipolar or mixed families) had significantly lower Performance IQ scores than controls. The effect size was greatest in those with schizophrenia (difference 25.3, 95% CI 16.68 to 33.92), intermediate in patients with bipolar disorder from mixed families (difference 14.50, 95% CI 5.79 to 23.20) and least in patients with bipolar disorder from bipolar families (difference 10.43, 95% CI 2.50 to 18.37). Unaffected relatives from schizophrenia or mixed families were also significantly more impaired in terms of Performance IQ than controls. No trend to significance was found for the unaffected relatives from bipolar families. Patients with schizophrenia were also significantly more impaired than their own relatives. Although no significant differences between the unaffected relative groups were found, impairments were greatest in the unaffected relatives from schizophrenia families, intermediate in the unaffected relatives from mixed families and least in the unaffected relatives from bipolar families.
Memory
Scores on the ERBMT were lower in all patient and relative groups
compared with controls. There was no evidence of disease specificity among
affected individuals although unaffected relatives from
schizophrenia families were more impaired than unaffected
relatives from either bipolar families (difference 3.96,
95% CI 7.25 to 0.67) or mixed families (difference
4.11, 95% CI 7.25 to 0.97). Once WASI IQ was taken into
account, the nature of the results changed little. Controls performed better
than all other groups and, among affected participants, there was little
evidence of disease specificity. However, patients with bipolar disorder from
mixed families performed worse than their unaffected relatives
(difference 3.8, 95% CI 0.5 to 7.1).
Executive function
No difference was found between the groups in terms of performance on the
Hayling Sentence Completion Test (HSCT;
Burgess & Shallice, 1996), whether controlled for current IQ or not. Total verbal fluency and performance
on the Stockings of Cambridge test
(Sahakian & Owen, 1992)
differed among the groups in the non-IQ-controlled analysis. Patients from all
groups performed worse in terms of verbal fluency and the Stockings of
Cambridge test than controls. Unaffected relatives from either
schizophrenia or mixed families also performed
significantly worse than controls on the Stockings of Cambridge test. Once
these analyses were adjusted for current intellectual function, no significant
difference remained.
Psychomotor performance
The number of correct substitutions on the DigitSymbol Substitution
Test (DSST; Erber, 1976)
differed significantly between groups (F(6,64)=4.81,
P=0.0004). All patient groups were impaired relative to controls.
Similarly, unaffected relatives from all families made fewer correct
substitutions than controls, although only unaffected relatives from
schizophrenia families performed significantly worse than
controls (difference 6.91, 95% CI 0.94 to 12.87). Patients with schizophrenia
did significantly worse than their unaffected relatives (difference 10.6, 95%
CI 3.7 to 17.5) and showed a tendency to do worse than the other patient
groups. There was no evidence of a difference between patients from
mixed or bipolar families.
Simple reaction time differed significantly between groups. All patient groups were significantly impaired compared with controls, although no difference was found between controls and any unaffected relative group. Patients with bipolar disorder from mixed families did significantly worse than those from bipolar families (difference 56.41, 95% CI 104.94 to 7.89). Patients with schizophrenia and patients with bipolar disorder from mixed families did significantly worse than their unaffected relatives.
Choice reaction time also differed between groups. All patient groups were significantly impaired compared with controls, although no difference was found between the control group and any unaffected relative group. Patients with schizophrenia performed less well than their unaffected relatives (difference 77.93, 95% CI 30.11 to 125.76) and patients with bipolar disorder also did less well than their unaffected relatives (difference 104.70, 95% CI 178.79 to 30.61). However, no significant difference was found between patients with bipolar disorder from mixed families and their unaffected relatives. Differences between affected or unaffected groups showed no diagnostic or familial specificity.
Effects of medication and weekly alcohol consumption
There was no statistically significant association between weekly alcohol
consumption, prescribed daily lithium or conventional antipsychotic dosages
and any measure of psychomotor performance.
Relationship of neuropsychology to genetic liability
The relationship of measures of intellectual and mnemonic function (NART IQ
and WASI Full-Scale, Verbal and Performance IQ scores) to genetic liability
was computed for all six groups where there was a family history of
psychiatric disorder. Within the group of patients with schizophrenia, genetic
liability to schizophrenia was inversely related to NART IQ (r=
70.49, P=0.01), WASI Full-Scale IQ (r= 0.33,
P=0.1) and WASI Verbal IQ (r=0.55, P=0.004)
(Fig. 2) but not WASI
Performance IQ (r=0.01, P=0.94). However, within the
unaffected relatives from schizophrenia families, genetic
liability to schizophrenia was positively related to Performance IQ
(r=0.45, P 0.03) (Fig.
3) and Full-Scale IQ (r=0.36, P=0.08, trend
only). No relationship was found between NART IQ (r=0.31,
P=0.13) or WASI Verbal IQ and genetic liability (r=0.06,
P=0.78).
|
|
Within the group of patients with bipolar disorder from mixed families there was no significant relationship between genetic liability to schizophrenia and measures of IQ, and no suggestion of any trend. Within unaffected relatives from mixed families, genetic liability was not related to NART IQ or WASI Full-Scale or Performance IQ; however, WASI Verbal IQ showed a trend to a negative association with genetic liability to schizophrenia (r=0.39, P=0.05). There was no evidence of a relationship between genetic liability to schizophrenia and scores on the ERBMT within any group. There was no evidence of a relationship between genetic liability to bipolar disorder and any measure of IQ within the groups of patients with bipolar disorder from bipolar families, their unaffected relatives or patients with bipolar disorder from mixed families. However, unaffected relatives from mixed families showed negative associations between genetic liability to bipolar disorder and WASI Full-Scale (r=0.50, P=0.009), Verbal IQ (r=0.47, P=0.01) and Performance IQ (r=0.40, P=0.04), but not NART IQ. There was no evidence of a relationship between genetic liability to bipolar disorder and scores on the ERBMT within any group.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This study did not find an overall difference in executive function across the groups. Post hoc testing revealed possible impairments in verbal fluency within all patient groups and reductions in planning ability (Stockings of Cambridge test) in all patients and in unaffected individuals with at least one relative with schizophrenia. However, neither of these findings survived correction for current intellectual function.
These findings suggest that intellectual function, planning ability and psychomotor tests with a high cognitive component are preferentially impaired in the relatives of people with schizophrenia. The fact that, among relatives of people with schizophrenia, Verbal IQ is positively related to a genetic liability to schizophrenia is somewhat counterintuitive. However, it finds precedent in an earlier study showing that obligate carriers (unaffected people who appear to transmit a parental diagnosis of schizophrenia to their offspring) of schizophrenia had a higher IQ than controls (Steel et al, 2002). Since our sample included people who will develop schizophrenia or other psychiatric illnesses in later years, it is possible that their inclusion explains the reduced mean IQ in this group overall. Furthermore, the positive association between IQ and genetic liability provides some evidence that genes for schizophrenia may convey an advantage in unaffected individuals.
Strengths and weaknesses of the study
All groups were well balanced in terms of age, gender, paternal social
class and weekly alcohol consumption. A history of compulsory education only
or less was more common both in patients with schizophrenia and in their
unaffected relatives than in the other five groups. Although all groups had
relatively low scores on the HRSD, YMRS and PANSS, none of the groups was
symptom-free and most patients were taking medication. However, allowance for
current symptoms was made at the analysis stage and none of the remaining
variation in test scores could be accounted for by medication.
Relationship to other research
This study confirms others that suggest that intellectual deficits are
related to a genetic liability to schizophrenia, but is one of the few to
study contemporaneously patients with schizophrenia and bipolar disorder. The
positive association between genetic liability to schizophrenia and IQ in
unaffected relatives is novel, as far as we know.
Studies of patients with schizophrenia (Aleman et al, 1999) and bipolar disorder (Quraishi & Frangou, 2002) have shown reductions in memory compared with controls which are also evident in direct comparisons (Seidman et al, 2002; McClellan et al, 2004) and are of similar magnitude regardless of diagnosis. However, the propensity of psychotropic medication and symptoms to confound these results has rarely been investigated.
For the HSCT, no difference was observed between any groups and controls for overall scaled score or error score. This finding is in contrast to several others, including one from the Edinburgh High-Risk Study (Byrne et al, 2003). However, patients in our study were on average 1020 years older than those in the Edinburgh study. The unaffected sample therefore includes fewer people likely to develop psychosis in future.
Deficits in cognitive tasks with a high attentional component have previously been found in the relatives of patients with schizophrenia (Pogue-Geile et al, 1991; Franke et al, 1993). This has suggested to some that attentional deficits may be a mechanism by which schizophrenia might develop. The finding of attentional deficits in unaffected individuals with relatives with schizophrenia supports this view. However, their presence in people with bipolar disorder suggests that once the disease is apparent, attentional deficits show no diagnostic specificity and may possibly act to maintain psychiatric symptoms regardless of the factors leading to their development.
Future work
Although our study examined groups of people with functional
psychosis, it is unclear whether the differences observed relate only
to diagnosis or whether they relate to psychotic symptoms. Most people
included in this study had such symptoms, although the numbers involved do not
allow enough statistical power to perform sensitivity analyses. It has also
been suggested that dimensions of psychotic symptoms found in affected
individuals represent the extremes of a range of variation within the
population as a whole. Brain anatomy and physiology may be more closely
related to these dimensions than to diagnosis. A future study could usefully
re-examine symptom dimensions in a range of people with psychotic illness and
relate these findings to neuro-psychological test performance, brain structure
and perhaps function.
![]() |
APPENDIX |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Premorbid intellectual function
National Adult Reading Test (Nelson,
1982).
Memory
Extended Rivermead Behavioural Memory Test, version A
(de Wall et al,
1994).
Executive function
Psychomotor performance
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
ACKNOWLEDGMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSMIV). Washington, DC: APA.
Burgess, P. W. & Shallice, T. (1996) Response suppression, initiation and strategy use following frontal lobe lesions. Neuropsychologica, 34, 263 272.[CrossRef]
Byrne, M., Clafferty, B. A., Cosway, R., et al (2003) Neuropsychology, genetic liability and psychotic symptoms in those at high risk of schizophrenia. Journal of Abnormal Psychology, 112, 38 48.[CrossRef][Medline]
Cannon, T. D., Mednick, S. A., Parnas, J., et al (1994) Developmental brain abnormalities in the offspring of schizophrenic mothers. II. Structural brain characteristics of schizophrenia and schizotypal personality disorder. Archives of General Psychiatry, 51, 955 962.[Abstract]
David, A. S., Malmberg, A., Brandt, L., et al (1997) IQ and risk for schizophrenia: a population-based cohort study. Psychological Medicine, 27, 1311 1323.[CrossRef][Medline]
de Wall, C., Wilson, B. A. & Baddeley, A. D. (1994) The Extended Rivermead Behavioural Memory Test: a measure of everyday memory performance in normal adults. Memory, 2, 149 166.[Medline]
Endicott, J. & Spitzer, R. L. (1978) A diagnostic interview: the schedule for affective disorders and schizophrenia. Archives of General Psychiatry, 36, 837 844.
Erber, J. T. (1976) Age differences in learning and memory on a digitsymbol substitution task. Experimental Aging Research, 2, 45 53.[Medline]
Franke, P., Maier, W., Hardt, J., et al (1993) Cognitive functioning and anhedonia in subjects at risk for schizophrenia. Schizophrenia Research, 10, 77 84.[CrossRef][Medline]
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56 62.[Medline]
Heinrichs, R.W. & Zakzanis, K. K. (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology, 12, 426 426.[CrossRef][Medline]
Johnson-Selfridge, M. & Zalewski, C. (2001) Moderator variables of executive functioning in schizophrenia: meta-analytic findings. Schizophrenia Bulletin, 27, 305 316.[Medline]
Kay, S. R., Fiszbein, A. & Opler, L. A. (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13, 261 276.[Medline]
Lawrie, S. M., Whalley, H. C., Abukmeil, S. S., et al (2001) Brain structure, genetic liability and psychotic symptoms in subjects at high risk of developing schizophrenia. Biological Psychiatry, 49, 811 823.[Medline]
McClellan, J., Prezbindowski, A., Brieger, D., et al (2004) Neuropsychological functioning in early onset psychotic disorders. Schizophrenia Research, 68, 21 26.[CrossRef][Medline]
McGuffin, P., Farmer, A. & Harvey, L. (1991) A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Archives of General Psychiatry, 48, 764 770.[CrossRef][Medline]
Nelson, H. E. (1982) National Adult Reading Test (NART): Test Manual. Windsor: NFERNelson.
Pearson, K. & Lee, A. (1901) On the inheritance of characteristics not capable of exact quantitative measurement. Philosophical Transactions of the Royal Society of London Series A, 195, 79 150.
Pogue-Geile, M. F., Garrett, A. H., Brunke, J. J., et al (1991) Neuropsychological impairments are increased in siblings of schizophrenic patients (abstract). Schizophrenia Research, 4, 390 .[CrossRef]
Quraishi, S. & Frangou, S. (2002) Neuropsychology of bipolar disorder: a review. Journal of Affective Disorders, 72, 209 226.[CrossRef][Medline]
Robertson, G. & Taylor, P. J. (1985) Some cognitive correlates of affective disorders. Psychological Medicine, 15, 297 309.[Medline]
Sahakian, B. J. & Owen, A. M. (1992) Computerised assessment in neuropsychiatry using CANTAB. Journal of the Royal Society of Medicine, 85, 399 402.[Medline]
Seidman, L. J., Kremen, W. S., Koren, D., et al (2002) A comparative profile analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses. Schizophrenia Research, 53, 31 44.[CrossRef][Medline]
Spreen, D. & Strauss, E. (1991) A Compendium of Neuropsychological Tests. New York: Oxford University Press.
Steel, R., Whalley, H. C., Miller, P., et al
(2002) Structural MRI of the brain in presumed carriers of
genes for schizophrenia, their affected and unaffected siblings.
Journal of Neurology, Neurosurgery and Psychiatry,
72, 455
458.
Wechsler, D. (1999) Wechsler Abbreviated Scale of Intelligence (WASI). San Antonio, TX: Harcourt Assessment.
Wing, J. K., Cooper, J. E. & Sartorius, N. (1974) The Description and Classification of Psychiatric Symptoms. An Instruction Manual for the PSE and Catego Systems. Cambridge: Cambridge University Press.
Young, R. C., Biggs, J. T., Ziegler, V. E., et al (1978) A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429 435.[Abstract]
Received for publication April 2, 2004. Revision received September 14, 2004. Accepted for publication September 30, 2004.
Read all eLetters
eLetters:
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Psychiatric Bulletin | Advances in Psychiatric Treatment | All RCPsych Journals |