Cognitive performance in presumed obligate carriers for psychosis

We report cognitive performance of a group of individuals whoare likely to have transmitted liability to psychosis to theiroffspring. Out of 230 relatives of patients with psychosis,27 met our criteria for a presumed obligate carrier, that isa non-psychotic individual who had a parent or a sibling aswell as an offspring with psychosis. The presumed obligate carriers showed impairments in verbal memory and in visuospatial manipulations, suggesting that these individuals transmit vulnerability forpsychosis to their offspring in terms of a disability to recallverbal information and an impaired capacity to perceive spatialrelations.

INTRODUCTION

TOP

INTRODUCTION

Deficits in cognition may represent a genetic vulnerabilityfor schizophrenia because cognitive deficits, particularlyin verbal learning and memory, are found in both individualswith schizophrenia and their healthy relatives (Byrne et al, 2003; Toulopoulou et al, 2003a, b). A similar pattern hasemerged in bipolar disorder, with both patients and their healthy relatives showing decreased performance in certain aspectsof cognition (Keri et al, 2001). The distinction of psychosisinto schizophrenia and bipolar disorder has been increasinglyquestioned, with recent evidence suggesting that the two disordersshare some common characteristics in terms of cognition andgenetic liability (Murray et al, 2004). We explore furtherthe idea that specific cognitive dysfunction may be a markerof genetic susceptibility to psychosis by assessing a veryselected group of relatives derived from a large sample of pedigreescontaining multiple cases of psychosis. The relatives had passedthe normal age threshold for developing psychosis (mean age=57.2years, s.d.=6.5) and, although healthy themselves, the structureof their pedigrees suggests that they are likely carriers ofsusceptibility genes for psychosis.

METHOD

TOP

METHOD

Participants and procedures
Our sample comprised a subgroup of first-degree relatives (n=27) of individuals with schizophrenia or bipolar I disorder withpsychotic features. The subgroup had been identified as beingmore likely to have transmitted the liability to schizophreniaand/or bipolar disorder (obligate carriers for psychosis) because,although healthy themselves, they have a parent or sibling,as well as an offspring, with schizophrenia or bipolar I disorder.The sample constitutes a sub-population of a larger cohort of relatives of individuals with schizophrenia, bipolar disorderand controls from the Maudsley Family Study of Psychosis (Toulopoulouet al, 2003a, b, 2005; McDonald et al, 2004). The 27 presumedobligate carriers were from a total of 230 non-psychotic relativeswho were neurocognitively assessed, and derived from 27 separate families. Eleven of these non-psychotic relatives were fromfamilies with documented multiple cases of schizophrenia, sixfrom families with documented multiple cases of bipolar disorder(with at least one member with bipolar I disorder with psychoticfeatures), and ten from families with documented cases of bothbipolar I disorder with psychotic features and schizophrenia.After complete description of the study to the participants,written informed consent was obtained. The study was approvedby the South London and Maudsley NHS Trust/Institute of PsychiatryEthical Committee (Research). A control group comprised 32individuals with no family history of schizophrenia or bipolardisorder, matched for age, gender, education and handedness.

Structured diagnostic interviews were administered to all participants using the Schedule for Affective Disorders and Schizophrenia–Lifetime version (Spitzer et al, 1978). Information regarding the timingand nature of any psychopathology was collected to enable DSM–IVdiagnoses to be made (American Psychiatric Association, 1994).Eight of the presumed obligate carriers had fulfilled criteriafor a DSM–IV Axis I disorder at some point in their lives,five for a major depressive disorder, two for panic disorderand one for anxiety disorder; one also fulfilled criteria forschizotypal personality disorder. Three of the controls hadalso fulfilled criteria for a major depressive disorder atsome point in their lives. All participants were recovered and were not in treatment at the time of assessment.

The neuropsychological tests assessed:

IQ, as measured by a five sub-test short form (vocabulary, similarities, comprehension, block design, object assembly) of the WechslerAdult Intelligence Scale–Revised (WAIS–R); Wechsler, 1981;and
verbal and visual memory and learning, as measuredby (i) immediaterecall, (ii) 30-min delayed recall and (iii)saving scoresof two stories and designs – two procedurestaken fromthe Wechsler Memory Scale (WMS; Wechsler & Stone, 1945).

The savings score was calculated using the following formula:saving score= (delayed recall/immediate recall)x100.

Data analyses
All data were analysed with independent-samples two-tailed t-tests except for handedness and gender where Pearson’s ${chi}$ ² tests were used. Analyses were performed primarily to compare thepresumed obligate carriers with the controls. We also re-ranall the analyses after excluding all those with a history ofpsychiatric disorder. We report findings without correctingfor multiple testing as we consider Bonferroni corrections too conservative since many of the tests are correlated and notindependent. Furthermore, although the presumed obligate sampleis abstracted from a very large population of relatives, thenumbers are sufficiently low to warrant initially less-stringentcriteria.

RESULTS

TOP

RESULTS

The groups were matched and therefore compatible in terms ofage (t=–0.66, d.f.=58, P=0.51), gender ( ${chi}$ ²=0.06, d.f.=1,P=0.81), education (t=–0.88, d.f.=57, P=0.38) and handedness ( ${chi}$ ²=2.5, d.f.=1, P=0.12). We found no differences between thepresumed obligate carriers for psychosis and the controls in estimated IQ and visual memory (Table 1). However, the presumedobligate carriers scored lower than the controls on objectassembly, a task that assesses perception of visual relationships,and on the delayed recall of verbal memory. A trend was also found for immediate recall of verbal memory to be poorer inobligate carriers. This became significant after excludingall those with a history of psychiatric disorder (t=2.86, d.f.=42,P=0.007). The differences in delayed recall of verbal memoryremained significant even after excluding all those with ahistory of psychiatric disorder (t=2.5, d.f.=41, P=0.02), butthe significant difference in the object assembly disappearedafter excluding those with a history of psychiatric disorder(t=1.8, d.f.=44, P=0.08).

View this table:
[in this window]
[in a new window]

Table 1 Current general intellectual and verbal and visual memory function (means (s.d.)) for presumed obligate carriers and normal controls

DISCUSSION

TOP

DISCUSSION

The presumed obligate carriers for psychosis represent a groupwho, although not suffering from psychosis themselves, arelikely to have transmitted to their offspring a liability topsychosis. This group had a similar IQ and educational attainmentto controls, with both groups falling within the average rangeof ability. However, they performed worse on object assembly,a test that evaluates visual – motor speed and visuospatial manipulation. Furthermore, the presumed obligate carriers showeddecreased performance in delayed recall of the logical memorysub-test, a test that assesses long-term verbal memory. Thesefindings remained statistically significant when we excludedthose with any Axis I disorder; moreover, when we excludedthose with an Axis I disorder differences between the immediate recall of the logical memory sub-test also became statisticallysignificant. Consistent with some studies of those with bipolardisorder and their relatives (Quraishi & Frangou, 2002)and of the relatives of those with schizophrenia (Laurent etal, 2000), visual memory was not impaired among our presumedobligate carrier subjects, suggesting that this does not reflectgenetic liability to psychosis.

To conclude, our data suggest that presumed obligate carriersfor psychosis transmit liability to their offspring in theform of impairments in verbal memory and ability to perceivespatial relationships. These impairments cannot be explainedby an overall decreased level of general intellectual abilityor by deprivations related to education.

ACKNOWLEDGMENTS

TOP

ACKNOWLEDGMENTS

E.B. and C.McD. were supported by research training fellowshipsfrom the Wellcome Trust.

REFERENCES

TOP