- Email: [email protected]
Sustained attention in bipolar I disorder patients with familial psychosis and their first-degree relatives
Psychiatry Research 199 (2012) 70–73
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
Sustained attention in bipolar I disorder patients with familial psychosis and their first-degree relatives Muriel Walshe a,1, Katja Kristina Schulze a,1, Daniel Stahl b, Mei-Hua Hall a,c, Christopher Chaddock a, Robin Morris d, Nicolette Marshall a, Colm McDonald a,e, Robin MacGregor Murray a, Elvira Bramon a, Eugenia Kravariti a,n a
Department of Psychosis Studies, PO Box 63, Institute of Psychiatry, King’s College London (KCL), De Crespigny Park, London SE5 8AF, UK Department of Biostatistics, Institute of Psychiatry, KCL, De Crespigny Park, London SE5 8AF, UK c Psychology Research Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA d Department of Psychology, Institute of Psychiatry, KCL, De Crespigny Park, London SE5 8AF, UK e Department of Psychiatry, Clinical Science Institute, National University of Ireland, Galway, Ireland b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 September 2011 Received in revised form 28 February 2012 Accepted 18 March 2012
Sustained attention (SA) was examined in patients with familial, psychotic Bipolar Disorder (BD) (n ¼43), their non-bipolar, non-psychotic relatives (n ¼44) and controls (n ¼ 47). Patients were impaired compared to relatives, but the latter did not differ from controls. Having a relative with familial, psychotic BD does not confer risk for SA deficits. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endophenotype Rapid visual processing Family study
1. Introduction Sustained attention (SA) deficits are valid endophenotypes (indicators of genetic vulnerability) for schizophrenia (Chen and Faraone, 2000; Cornblatt and Malhotra, 2001; Tsuang et al., 2006; Wang et al., 2007). The disorder shares genetic aetiology, phenomenology and cognitive deficits with bipolar disorder (BD) (Murray et al., 2004; The International Schizophrenia Consortium, 2009; Chen and Faraone, 2000; Kravariti et al., 2005; Godard et al., 2011), raising the possibility that SA deficits also mark the bipolar diathesis. Establishing SA deficits in unaffected relatives of BD patients is critical for demonstrating their endophenotypic potential (Gottesman and Gould, 2003). However, fewer than 15 studies have investigated SA in this population, with mixed results (Bora et al., 2008; Clark et al., 2005; Ferrier et al., 2004; Frantom et al., 2008; Glahn et al., 2010; Jabben et al., 2009; Kieseppa et al., 2005; Klimes-Dougan et al., 2006; Kremen et al., 1998; Kumar et al., 2010; Trivedi et al., 2008; Winter et al., 1981). No previous study has specifically examined SA in non-bipolar, non-psychotic relatives of patients with psychotic Bipolar I
n
Corresponding author. Tel.: þ44 207 8480331; fax: þ 44 207 8480287. E-mail address: [email protected] (E. Kravariti). 1 Dr Muriel Walshe and Dr Katja K. Schulze contributed equally to the manuscript (Joint First Authors). 0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.03.018
Disorder (BD-I) from families multiply affected with psychosis (multiplex families). Psychosis and familiality may critically enhance the salience of neurocognitive endophenotypes for BD. Indeed, psychotic BD has been reported to be cognitively indistinguishable from schizophrenia (Simonsen et al., 2011), and the focus on multiplex families reduces the potential of spurious or non-genetic illness forms (Glahn et al., 2010). We examined SA in BD-I patients with personal and family histories of psychosis, their non-bipolar, non-psychotic firstdegree relatives, and community controls. We predicted that relatives would perform intermediately to patients and controls, and that SA would correlate significantly with a continuous measure of genetic liability to psychosis. 2. Method 2.1. Participants The study included 43 BD-I outpatients, who had both a history of delusions or hallucinations during illness exacerbation, and one or more first/second-degree relative(s) with functional psychosis. It further included 44 of the patients’ firstdegree relatives with no personal history, and 47 unrelated community controls with no personal or family history (up to second-degree relatives) of psychotic, bipolar or schizophrenia-spectrum disorders. Lifetime diagnoses of non-psychotic, non-bipolar psychiatric disorders were not an exclusion factor for either controls or relatives.
M. Walshe et al. / Psychiatry Research 199 (2012) 70–73 All participants were characterised diagnostically according to DSM-IV criteria, using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Spitzer and Endicott, 1978). Medical notes were additionally consulted for most patients. Information regarding psychiatric diagnoses of family members not directly assessed was obtained from reliable informants using the Family Interview for Genetic Studies (Nurnberger et al., 1994), and, when available, from psychiatric notes. The Beck Depression Inventory (BDI) (Beck et al., 1961) and the Altman Self-Rated Mania Scale (ASRM) (Altman et al., 1997) were administered to all participants on the day of testing to assess current mood. Positive and Negative
71
Syndrome Scale (PANSS; Kay et al., 1987) ratings of psychotic and general psychopathology symptoms were available for a subgroup of 30 patients. All participants were Caucasian, aged 18–65 years, native speakers of English, with no histories of neurological disorder, organic brain disease, substance/alcohol dependency in the previous twelve months, or head trauma resulting in loss of consciousness for 45 minutes. No participant was acutely ill at testing. All subjects provided written informed consent and local Ethical Committees approved the study. This has been described in detail elsewhere (Schulze et al., 2011). The participants’ characteristics are summarised in Table 1.
Table 1 Socio-demographic, diagnostic, clinical and neuropsychological characteristics of the study groups. Variable
Patients
Female Parental Social Class I or II d DSM-IV Diagnosis Bipolar I Disorder Major Depression Substance-Induced Mood Disorder Drug Dependence Depressive Disorder NOS Generalised Anxiety Disorder Medication Antipsychotic Mood Stabilising Antidepressant Anticonvulsant None
Years Old at Testing Years of Education Years Old at Onset of BD-I e Years Old at Diagnosis of BD-I Years Since Onset of BD-I No. Hospitalisations Positive and Negative Syndrome Scale Positive Scale Negative Scale General Psychopathology Scale Beck Depression Inventory g,i Altman Self-Rating Mania Scale h,i
a
(n¼ 43)
Relatives
b
Controls (n¼47) Wald w2/F
(n¼ 44)
c
D.F.
P
Post-hoc contrasts
6.66 1.38 n/a
2 2 n/a
0.036 PA 4REnn 0.502 n/a
n/a
n/a
n/a
N
%
N
%
N
%
29 22
67.44 51.16
19 23
43.18 52.27
26 18
55.32 38.30
43 0 0 0 0 0
100.00 0.00 0.00 0.00 0.00 0.00
0 8 1 1 0 0
0.00 18.18 2.27 2.27 0.00 0.00
0 5 0 1 2 1
0.00 10.64 0.00 2.13 4.26 2.13
10 32 14 21 10
23.26 74.42 32.56 48.84 23.26
0 0 0 0 0
0.00 0.00 0.00 0.00 0.00
0 0 0 0 0
0.00 0.00 0.00 0.00 0.00
Mean
SD
Mean
SD
Mean
SD
44.95 14.35 23.44 26.44 21.51 4.70
11.22 3.10 6.49 9.14 11.10 4.95
46.82 14.84 n/a n/a n/a n/a
12.87 3.47 n/a n/a n/a n/a
44.81 15.02 n/a n/a n/a n/a
14.35 3.09 n/a n/a n/a n/a
0.36 0.58 n/a n/a n/a n/a
2, 79 2, 79 n/a n/a n/a n/a
0.701 0.563 n/a n/a n/a n/a
8.37 7.63 19.83 7.67 3.49
1.81 1.07 3.65 6.66 2.78
n/a n/a n/a 3.84 2.16
n/a n/a n/a 3.06 2.27
n/a n/a n/a 4.00 2.81
n/a n/a n/a 3.01 3.27
n/a n/a n/a 5.53 3.16
n/a n/a n/a 2, 79 2, 78
n/a n/a n/a 0.006 PA 4REnnn, PA4 COnn 0.048 PA 4REn
Mean
SD
Mean
SD
Mean
SD
115.11
9.92
0.86
2, 79 0.425
18.02 1.38 0.91 0.94 481.47
5.94 2.44 0.06 0.08 101.57
5.00 2.48 4.53 2.84 2.74
3, 3, 3, 3, 3,
f
WASI IQ Rapid Visual Processing No. Hits No. False Alarms Sensitivity (A0 ) Response Bias (B00 ) Response Latency
d
j
k
111.28 14.46
0.31
15.83 0.90 0.89 0.97 509.37
0.39 k 0.25 0.35 k 0.34 k 0.27 k
5.20 1.13 0.05 0.04 103.77
d
j
113.73 11.87 0.13
k
18.36 1.80 0.92 0.93 465.17
4.98 3.85 0.05 0.10 86.30
l
0.06 0.13 l 0.06 0.13 0.17
l
l l l
78 78 79 76 79
0.003 0.067 0.006 0.043 0.049
PA oREn PA oREn PA oREn Not significant (P 40.05)
PA: Patients; RE: Relatives; CO: Controls. a The index BD-I patients had family histories of Psychotic Bipolar I Disorder (21 families), Schizophrenia (6 families), Major Depressive Illness with Psychosis (3 families), Psychotic Bipolar I Disorder and Schizoaffective Disorder (2 families), Psychotic Bipolar I Disorder and Schizophrenia (1 family), Schizoaffective Disorder (1 family) and Psychotic Disorder Not Otherwise Specified (1 family) (35 families in total). b 12 parents, 26 siblings and 6 offspring of the index cases. c Wald w2 is reported for (N/%) ‘Female’, ‘Parental Social Class’ (N/% Class I or II), ‘DSM-IV Diagnosis’ and ‘Medication’; F is reported for the remaining variables. d Class I: Professional; Class II: Managerial/Technical. e Age at onset of Bipolar I Disorder was defined as age at first affective or psychotic symptoms. f Positive and Negative Syndrome Scale (PANSS) ratings were available for a subgroup of 30 patients (70% of the total patient sample). g Beck Depression Inventory score ranges: 0–9 (normal range), 10–19 (mild), 20–28 (moderate) and 29–63 (severe). h Altman Self Rating Mania Scale score ranges: 0–5 (not likely to be associated with manic or hypomanic symptoms), Z 6 (a high probability of manic or hypomanic symptoms). i Approximately half (49%) of the patients were euthymic, i.e. experienced normal levels of affective symptoms (BDI o 10 and ASRMo6), 26% reported mild or moderate depressive symptoms (BDI 10–28 and ASRMo6), 16% experienced hypomanic or manic symptoms (BDIo 10 and ASRM 6–9) and 9% reported mild or moderate mixed symptoms (BDI 10–28 and ASRM 6–9). j Cohen’s d (where appropriate, signs were reversed, so that positive effect sizes always denote worse performance, and negative effect sizes always denote better performance compared to controls.) k Small effect size (0.20 rd r 0.49). l negligible effect size ( 0.20o d o0.20). n P r 0.05. nn P r0.01. nnn Pr 0.001.
72
M. Walshe et al. / Psychiatry Research 199 (2012) 70–73
2.2. Measures Hits, False Alarms, Target Sensitivity (A0 : signal/noise discrimination), Response Bias (B0 : tendency to respond regardless of whether the target is present) and Mean Latency for Correct Responses from the CANTAB Rapid Visual Information Processing (RVIP) task (Cambridge Cognition, 2006) were used to assess SA. The RVIP was purposely selected as a widely used paradigm of the Continuous Performance Tests, which have detected SA deficits in unaffected relatives of schizophrenia patients (Chen and Faraone, 2000). IQ was estimated using Vocabulary and Matrix Reasoning of the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). Genetic loading (GL) on psychosis was estimated for patients and relatives using a continuous measure that assumes a liability threshold model of genetic disease. This has been described elsewhere (McDonald et al., 2004). To avoid a bimodal distribution (patients score higher than relatives), we calculated standardised (Z) scores for each group [(GL score—mean)/sd] before pooling the scores together. 2.3. Statistical analysis Group differences in the study measures were examined using regression analyses for clustered observations in the programme STATA v.10.0 for Windows (StataCorp, 2007). The cluster option provides robust variance estimators that adjust for within-cluster correlations (each family being a separate ‘cluster’) and safeguards against potential violations of the standard regression assumptions (Williams, 2000). The SA analysis controlled for gender [which both predicted SA performance in the total study sample (P o0.05) and differed significantly across groups: see Results]. Associations between SA and symptom ratings or GL scores were examined using cluster linear regression analyses. For each neuropsychological variable we further estimated the standardized mean difference (effect size) between patients or relatives and controls using Cohen’s d (d ¼M cases/relatives—M controls/ pooled s).
3. Results The results of the statistical group comparisons are summarised in Table 1. Significant differences emerged for gender (there were more females among the patients than the relatives), BDI/ASRM scores (patients scored higher than either/both of the other groups), and sustained attention, with patients showing impaired hits, sensitivity and response bias compared to relatives (Table 1). The pattern and significance of these RVIP differences did not change after excluding from the analysis controls (n¼8), or relatives and controls (n ¼18) with DSM-IV diagnoses. The patients showed small (0.20rdr0.49) and the relatives negligible ( 0.20od o0.20) effect sizes in all cognitive measures. In the full study sample and/or the combined patient/relative groups, higher BDI scores were associated with increased response latency, and higher ASRM scores with increased response bias and false alarms (Po0.05). In the patient sample, PANSS negative symptoms were associated with reduced response bias and increased false alarms (Po0.05). GL scores did not correlate significantly with any RVIP measure (P40.10).
4. Discussion This is the first study to examine sustained attention in nonbipolar, non-psychotic relatives of patients with psychotic BD-I from multiplex families. The index cases showed SA deficits which were statistically significant compared to their relatives, but yielded small effect sizes compared to the controls. The relatives did not differ from controls in any SA measure. These findings were not due to confounding effects of IQ, persisted after excluding relatives/controls with psychiatric diagnoses, and contradicted our hypotheses. Extending this result, SA failed to show significant correlations with a continuous measure of genetic loading on psychosis. Our results indicate that sustained attention is an unlikely endophenotype for psychotic BD-I, since a core criterion for endophenotypes, i.e. presence in unaffected relatives (Gottesman
and Gould, 2003), was not satisfied in the present study, despite sampling patients with a form of BD-I (psychotic and familial) with increased homogeneity, clinical severity and presumed genetic and neuropsychological overlap with schizophrenia. Our findings further suggest that the preponderance of negative findings in the few relevant studies of unaffected relatives (Bora et al., 2008; Clark et al., 2005; Ferrier et al., 2004; Frantom et al., 2008; Glahn et al., 2010; Jabben et al., 2009; Kieseppa et al., 2005; Kumar et al., 2010) is unlikely to be an artefact of small or heterogeneous samples, or of the low discriminability of cognitive deficits in BD compared to schizophrenia (Krabbendam et al., 2005). Our findings are also in line with the absence of selective attention deficits (another candidate attentional endophenotype for BD-I) in a largely overlapping sample of first-degree relatives of BD-I patients reported on previously by our group (Kravariti et al., 2009; for other neurocognitive findings from this sample see Schulze et al. (2011)). Our broad source of patient ascertainment included both clinical and community settings. Therefore, we cannot exclude the possibility that a familial risk for SA deficits is confined to a subgroup of patients who are more likely to be found among in/out-patient cohorts. We conclude that being a first-degree relative of an individual with a severe form of bipolar I disorder with psychotic features, indexed from families multiply affected with psychosis, does not confer risk for sustained attention deficits. However, earlier findings of SA deficits in unaffected relatives of BD patients by a small number of studies (Kremen et al., 1998; Klimes-Dougan et al., 2006; Trivedi et al., 2008; Bora et al., 2009) suggest that further research is needed to clarify the endophenotypic potential of SA deficits in bipolar disorder.
Acknowledgements MW and EK received funding support from the Psychiatry Research Trust. The work was funded by Guy’s and St. Thomas’ Charitable Foundation Research Studentship to KS. We would like to thank the Manic Depression Fellowship for help with recruitment of participants and also all the families who took part in this research.
References Altman, E.G., Hedeker, D., Peterson, J.L., Davis, J.M., 1997. The Altman self-rating mania scale. Biological Psychiatry 42, 948–955. Beck, A., Ward, C., Mendelson, M., Mock, J., Erbaugh, J., 1961. An inventory for measuring depression. Archives of General Psychiatry 4, 561–571. Bora, E., Yucel, M., Pantelis, C., 2009. Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. Journal of Affective Disorders 113, 1–20. Bora, E., Vahip, S., Akdeniz, F., Ilerisoy, H., Aldemir, E., Alkan, M., 2008. Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder. Psychiatry Research 161, 318–324. Cambridge Cognition, 2006. Cambridge Neuropsychological Test Automated Battery (CANTAB). Chen, W., Faraone, S., 2000. Sustained attention deficits as markers of genetic susceptibility to schizophrenia. American Journal of Medical Genetics 97, 52–57. Clark, L., Kempton, M., Scarna , A., Grasby, P., Goodwin, G., 2005. Sustained attention-deficit confirmed in euthymic bipolar disorder but not in firstdegree relatives of bipolar patients or euthymic unipolar depression. Biological Psychiatry 57, 183–187. Cornblatt, B., Malhotra, A., 2001. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. American Journal of Medical Genetics 105, 11–15. Ferrier, I., Chowdhury, R., Thompson, J., Watson, S., Young, A., 2004. Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disorders 6, 319–322. Frantom, L., Allen, D., Cross, C., 2008. Neurocognitive endophenotypes for bipolar disorder. Bipolar Disorders 10, 387–399.
M. Walshe et al. / Psychiatry Research 199 (2012) 70–73
Glahn, D.C., Almasy, L., Barguil, M., Hare, E., Peralta, J.M., Kent Jr, J.W., Dassori, A., Contreras, J., Pacheco, A., Lanzagorta, N., Nicolini, H., Raventos, H., Escamilla, M.A., 2010. Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families. Archives of General Psychiatry 67, 168–177. Godard, J., Grondin, S., Baruch, P., Lafleur, M.F., 2011. Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder. Psychiatry Research 190, 244–252. Gottesman, I., Gould, T., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636–645. Jabben, N., Arts, B., Krabbendam, L., Van Os, J., 2009. Investigating the association between neurocognition and psychosis in bipolar disorder: further evidence for the overlap with schizophrenia. Bipolar Disorders 11, 166–177. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276. Kieseppa, T., Tuulio-Henriksson, A., Haukka, J., Van Erp, T., Glahn, D., Cannon, T., Partonen, T., Kaprio, J., Lonnqvist, J., 2005. Memory and verbal learning functions in twins with bipolar-I disorder, and the role of informationprocessing speed. Psychological Medicine 35, 205–215. Klimes-Dougan, B., Ronsaville, D., Wiggs, E.A., Martinez, P.E., 2006. Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders. Biological Psychiatry 60, 957–965. Krabbendam, L., Arts, B., van Os, J., Aleman, A., 2005. Cognitive functioning in patients with schizophrenia and bipolar disorder: a quantitative review. Schizophrenia Research 80, 137–149. Kravariti, E., Dixon, T., Frith, C., Murray, R.M., McGuire, P., 2005. Association of symptoms and executive function in schizophrenia and bipolar disorder. Schizophrenia Research 74, 221–231. Kravariti, E., Schulze, K., Kane, F., Kalidindi, S., Bramon, E., Walshe, M., Marshall, N., Hall, M.H., Georgiades, A., McDonald, C., Murray, R.M., 2009. Stroop-test interference in bipolar disorder. British Journal of Psychiatry 194, 285–286. Kremen, W., Faraone, S., Seidman, L., Pepple, J., Tsuang, M., 1998. Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands. Psychiatry Research 79, 227–240. Kumar, C.T.S., Christodoulou, T., Vyas, N.S., Kyriakopoulos, M., Corrigall, R., Reichenberg, A., Frangou, S., 2010. Deficits in visual sustained attention differentiate genetic liability and disease expression for Schizophrenia from bipolar disorder. Schizophrenia Research 124, 152–160. McDonald, C., Bullmore, E., Sham, P., Chitnis, X., Wickham, H., Bramon, E., Murray, R.M., 2004. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Archives of General Psychiatry 61, 974–984.
73
Murray, R.M., Sham, P., van Os, J., Zanelli, J., Cannon, M., McDonald, C., 2004. A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophrenia Research 71, 405–416. Nurnberger, J.I., Blehar, M.C., Kaufmann, C.A., York-Cooler, C., Simpson, S.G., Harkavy-Friedman, J., Severe, J.B., Malaspina, D., Reich, T., 1994. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Archives of General Psychiatry 51, 849–859. Schulze, K., Walshe, M., Stahl, D., Kravariti, E., Morris, R.G., Marshall, N., Hall, M.-H., Murray, R.M., Bramon, E., 2011. Executive functioning in familial bipolar I disorder patients and their unaffected relatives. Bipolar Disorders 13, 208–216. Simonsen, C., Sundet, K., Vaskinn, A., Birkenaes, A., Engh, J., Faerden, A., Jonsdottir, H., Ringen, P., Opjordsmoen, S., Melle, I., Friis, S., Andreassen, O., 2011. Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophrenia Bulletin 37, 73–83. Spitzer, R., Endicott, J., 1978. Schedule for Affective Disorders and SchizophreniaLifetime Version. New York State Psychiatric Institute, New York. StataCorp, 2007. STATA v.10.0 for Windows. The International Schizophrenia Consortium, 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752. Trivedi, J., Goel, D., Dhyani, M., Sharma, S., Singh, A., Sinha, P.R.T., 2008. Neurocognition in first-degree healthy relatives (siblings) of bipolar affective disorder patients. Psychiatry and Clinical Neurosciences 62, 190–196. Tsuang, H., Lin, S., Liu, S., Hsieh, M., Hwang, T., Liu, C., Hwu, H., Chen, W., 2006. More severe sustained attention deficits in nonpsychotic siblings of multiplex schizophrenia families than in those of simplex ones. Schizophrenia Research 87, 172–180. Wang, Q., Chan, R., Sun, J., Yao, J., Deng, W., Sun, X., Liu, X., Sham, P., Ma, X., Meng, H., Murray, R.M., Collier, D., Li, T., 2007. Reaction time of the continuous performance test is an endophenotypic marker for schizophrenia: a study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls. Schizophrenia Research 89, 293–298. Wechsler, D., 1999. Wechsler abbreviated scale of intelligence (WASI). The Psychological Corporation. Williams, R., 2000. A note on robust variance estimation for cluster-correlated data. Biometrics 56, 645–646. Winter, K., Stone, A., Weintraub, S., Neale, J., 1981. Cognitive and attentional deficits in children vulnerable to psychopathology. Journal of Abnormal Child Psychology 9, 435–453.
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
Sustained attention in bipolar I disorder patients with familial psychosis and their first-degree relatives Muriel Walshe a,1, Katja Kristina Schulze a,1, Daniel Stahl b, Mei-Hua Hall a,c, Christopher Chaddock a, Robin Morris d, Nicolette Marshall a, Colm McDonald a,e, Robin MacGregor Murray a, Elvira Bramon a, Eugenia Kravariti a,n a
Department of Psychosis Studies, PO Box 63, Institute of Psychiatry, King’s College London (KCL), De Crespigny Park, London SE5 8AF, UK Department of Biostatistics, Institute of Psychiatry, KCL, De Crespigny Park, London SE5 8AF, UK c Psychology Research Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA d Department of Psychology, Institute of Psychiatry, KCL, De Crespigny Park, London SE5 8AF, UK e Department of Psychiatry, Clinical Science Institute, National University of Ireland, Galway, Ireland b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 September 2011 Received in revised form 28 February 2012 Accepted 18 March 2012
Sustained attention (SA) was examined in patients with familial, psychotic Bipolar Disorder (BD) (n ¼43), their non-bipolar, non-psychotic relatives (n ¼44) and controls (n ¼ 47). Patients were impaired compared to relatives, but the latter did not differ from controls. Having a relative with familial, psychotic BD does not confer risk for SA deficits. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endophenotype Rapid visual processing Family study
1. Introduction Sustained attention (SA) deficits are valid endophenotypes (indicators of genetic vulnerability) for schizophrenia (Chen and Faraone, 2000; Cornblatt and Malhotra, 2001; Tsuang et al., 2006; Wang et al., 2007). The disorder shares genetic aetiology, phenomenology and cognitive deficits with bipolar disorder (BD) (Murray et al., 2004; The International Schizophrenia Consortium, 2009; Chen and Faraone, 2000; Kravariti et al., 2005; Godard et al., 2011), raising the possibility that SA deficits also mark the bipolar diathesis. Establishing SA deficits in unaffected relatives of BD patients is critical for demonstrating their endophenotypic potential (Gottesman and Gould, 2003). However, fewer than 15 studies have investigated SA in this population, with mixed results (Bora et al., 2008; Clark et al., 2005; Ferrier et al., 2004; Frantom et al., 2008; Glahn et al., 2010; Jabben et al., 2009; Kieseppa et al., 2005; Klimes-Dougan et al., 2006; Kremen et al., 1998; Kumar et al., 2010; Trivedi et al., 2008; Winter et al., 1981). No previous study has specifically examined SA in non-bipolar, non-psychotic relatives of patients with psychotic Bipolar I
n
Corresponding author. Tel.: þ44 207 8480331; fax: þ 44 207 8480287. E-mail address: [email protected] (E. Kravariti). 1 Dr Muriel Walshe and Dr Katja K. Schulze contributed equally to the manuscript (Joint First Authors). 0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.03.018
Disorder (BD-I) from families multiply affected with psychosis (multiplex families). Psychosis and familiality may critically enhance the salience of neurocognitive endophenotypes for BD. Indeed, psychotic BD has been reported to be cognitively indistinguishable from schizophrenia (Simonsen et al., 2011), and the focus on multiplex families reduces the potential of spurious or non-genetic illness forms (Glahn et al., 2010). We examined SA in BD-I patients with personal and family histories of psychosis, their non-bipolar, non-psychotic firstdegree relatives, and community controls. We predicted that relatives would perform intermediately to patients and controls, and that SA would correlate significantly with a continuous measure of genetic liability to psychosis. 2. Method 2.1. Participants The study included 43 BD-I outpatients, who had both a history of delusions or hallucinations during illness exacerbation, and one or more first/second-degree relative(s) with functional psychosis. It further included 44 of the patients’ firstdegree relatives with no personal history, and 47 unrelated community controls with no personal or family history (up to second-degree relatives) of psychotic, bipolar or schizophrenia-spectrum disorders. Lifetime diagnoses of non-psychotic, non-bipolar psychiatric disorders were not an exclusion factor for either controls or relatives.
M. Walshe et al. / Psychiatry Research 199 (2012) 70–73 All participants were characterised diagnostically according to DSM-IV criteria, using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Spitzer and Endicott, 1978). Medical notes were additionally consulted for most patients. Information regarding psychiatric diagnoses of family members not directly assessed was obtained from reliable informants using the Family Interview for Genetic Studies (Nurnberger et al., 1994), and, when available, from psychiatric notes. The Beck Depression Inventory (BDI) (Beck et al., 1961) and the Altman Self-Rated Mania Scale (ASRM) (Altman et al., 1997) were administered to all participants on the day of testing to assess current mood. Positive and Negative
71
Syndrome Scale (PANSS; Kay et al., 1987) ratings of psychotic and general psychopathology symptoms were available for a subgroup of 30 patients. All participants were Caucasian, aged 18–65 years, native speakers of English, with no histories of neurological disorder, organic brain disease, substance/alcohol dependency in the previous twelve months, or head trauma resulting in loss of consciousness for 45 minutes. No participant was acutely ill at testing. All subjects provided written informed consent and local Ethical Committees approved the study. This has been described in detail elsewhere (Schulze et al., 2011). The participants’ characteristics are summarised in Table 1.
Table 1 Socio-demographic, diagnostic, clinical and neuropsychological characteristics of the study groups. Variable
Patients
Female Parental Social Class I or II d DSM-IV Diagnosis Bipolar I Disorder Major Depression Substance-Induced Mood Disorder Drug Dependence Depressive Disorder NOS Generalised Anxiety Disorder Medication Antipsychotic Mood Stabilising Antidepressant Anticonvulsant None
Years Old at Testing Years of Education Years Old at Onset of BD-I e Years Old at Diagnosis of BD-I Years Since Onset of BD-I No. Hospitalisations Positive and Negative Syndrome Scale Positive Scale Negative Scale General Psychopathology Scale Beck Depression Inventory g,i Altman Self-Rating Mania Scale h,i
a
(n¼ 43)
Relatives
b
Controls (n¼47) Wald w2/F
(n¼ 44)
c
D.F.
P
Post-hoc contrasts
6.66 1.38 n/a
2 2 n/a
0.036 PA 4REnn 0.502 n/a
n/a
n/a
n/a
N
%
N
%
N
%
29 22
67.44 51.16
19 23
43.18 52.27
26 18
55.32 38.30
43 0 0 0 0 0
100.00 0.00 0.00 0.00 0.00 0.00
0 8 1 1 0 0
0.00 18.18 2.27 2.27 0.00 0.00
0 5 0 1 2 1
0.00 10.64 0.00 2.13 4.26 2.13
10 32 14 21 10
23.26 74.42 32.56 48.84 23.26
0 0 0 0 0
0.00 0.00 0.00 0.00 0.00
0 0 0 0 0
0.00 0.00 0.00 0.00 0.00
Mean
SD
Mean
SD
Mean
SD
44.95 14.35 23.44 26.44 21.51 4.70
11.22 3.10 6.49 9.14 11.10 4.95
46.82 14.84 n/a n/a n/a n/a
12.87 3.47 n/a n/a n/a n/a
44.81 15.02 n/a n/a n/a n/a
14.35 3.09 n/a n/a n/a n/a
0.36 0.58 n/a n/a n/a n/a
2, 79 2, 79 n/a n/a n/a n/a
0.701 0.563 n/a n/a n/a n/a
8.37 7.63 19.83 7.67 3.49
1.81 1.07 3.65 6.66 2.78
n/a n/a n/a 3.84 2.16
n/a n/a n/a 3.06 2.27
n/a n/a n/a 4.00 2.81
n/a n/a n/a 3.01 3.27
n/a n/a n/a 5.53 3.16
n/a n/a n/a 2, 79 2, 78
n/a n/a n/a 0.006 PA 4REnnn, PA4 COnn 0.048 PA 4REn
Mean
SD
Mean
SD
Mean
SD
115.11
9.92
0.86
2, 79 0.425
18.02 1.38 0.91 0.94 481.47
5.94 2.44 0.06 0.08 101.57
5.00 2.48 4.53 2.84 2.74
3, 3, 3, 3, 3,
f
WASI IQ Rapid Visual Processing No. Hits No. False Alarms Sensitivity (A0 ) Response Bias (B00 ) Response Latency
d
j
k
111.28 14.46
0.31
15.83 0.90 0.89 0.97 509.37
0.39 k 0.25 0.35 k 0.34 k 0.27 k
5.20 1.13 0.05 0.04 103.77
d
j
113.73 11.87 0.13
k
18.36 1.80 0.92 0.93 465.17
4.98 3.85 0.05 0.10 86.30
l
0.06 0.13 l 0.06 0.13 0.17
l
l l l
78 78 79 76 79
0.003 0.067 0.006 0.043 0.049
PA oREn PA oREn PA oREn Not significant (P 40.05)
PA: Patients; RE: Relatives; CO: Controls. a The index BD-I patients had family histories of Psychotic Bipolar I Disorder (21 families), Schizophrenia (6 families), Major Depressive Illness with Psychosis (3 families), Psychotic Bipolar I Disorder and Schizoaffective Disorder (2 families), Psychotic Bipolar I Disorder and Schizophrenia (1 family), Schizoaffective Disorder (1 family) and Psychotic Disorder Not Otherwise Specified (1 family) (35 families in total). b 12 parents, 26 siblings and 6 offspring of the index cases. c Wald w2 is reported for (N/%) ‘Female’, ‘Parental Social Class’ (N/% Class I or II), ‘DSM-IV Diagnosis’ and ‘Medication’; F is reported for the remaining variables. d Class I: Professional; Class II: Managerial/Technical. e Age at onset of Bipolar I Disorder was defined as age at first affective or psychotic symptoms. f Positive and Negative Syndrome Scale (PANSS) ratings were available for a subgroup of 30 patients (70% of the total patient sample). g Beck Depression Inventory score ranges: 0–9 (normal range), 10–19 (mild), 20–28 (moderate) and 29–63 (severe). h Altman Self Rating Mania Scale score ranges: 0–5 (not likely to be associated with manic or hypomanic symptoms), Z 6 (a high probability of manic or hypomanic symptoms). i Approximately half (49%) of the patients were euthymic, i.e. experienced normal levels of affective symptoms (BDI o 10 and ASRMo6), 26% reported mild or moderate depressive symptoms (BDI 10–28 and ASRMo6), 16% experienced hypomanic or manic symptoms (BDIo 10 and ASRM 6–9) and 9% reported mild or moderate mixed symptoms (BDI 10–28 and ASRM 6–9). j Cohen’s d (where appropriate, signs were reversed, so that positive effect sizes always denote worse performance, and negative effect sizes always denote better performance compared to controls.) k Small effect size (0.20 rd r 0.49). l negligible effect size ( 0.20o d o0.20). n P r 0.05. nn P r0.01. nnn Pr 0.001.
72
M. Walshe et al. / Psychiatry Research 199 (2012) 70–73
2.2. Measures Hits, False Alarms, Target Sensitivity (A0 : signal/noise discrimination), Response Bias (B0 : tendency to respond regardless of whether the target is present) and Mean Latency for Correct Responses from the CANTAB Rapid Visual Information Processing (RVIP) task (Cambridge Cognition, 2006) were used to assess SA. The RVIP was purposely selected as a widely used paradigm of the Continuous Performance Tests, which have detected SA deficits in unaffected relatives of schizophrenia patients (Chen and Faraone, 2000). IQ was estimated using Vocabulary and Matrix Reasoning of the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). Genetic loading (GL) on psychosis was estimated for patients and relatives using a continuous measure that assumes a liability threshold model of genetic disease. This has been described elsewhere (McDonald et al., 2004). To avoid a bimodal distribution (patients score higher than relatives), we calculated standardised (Z) scores for each group [(GL score—mean)/sd] before pooling the scores together. 2.3. Statistical analysis Group differences in the study measures were examined using regression analyses for clustered observations in the programme STATA v.10.0 for Windows (StataCorp, 2007). The cluster option provides robust variance estimators that adjust for within-cluster correlations (each family being a separate ‘cluster’) and safeguards against potential violations of the standard regression assumptions (Williams, 2000). The SA analysis controlled for gender [which both predicted SA performance in the total study sample (P o0.05) and differed significantly across groups: see Results]. Associations between SA and symptom ratings or GL scores were examined using cluster linear regression analyses. For each neuropsychological variable we further estimated the standardized mean difference (effect size) between patients or relatives and controls using Cohen’s d (d ¼M cases/relatives—M controls/ pooled s).
3. Results The results of the statistical group comparisons are summarised in Table 1. Significant differences emerged for gender (there were more females among the patients than the relatives), BDI/ASRM scores (patients scored higher than either/both of the other groups), and sustained attention, with patients showing impaired hits, sensitivity and response bias compared to relatives (Table 1). The pattern and significance of these RVIP differences did not change after excluding from the analysis controls (n¼8), or relatives and controls (n ¼18) with DSM-IV diagnoses. The patients showed small (0.20rdr0.49) and the relatives negligible ( 0.20od o0.20) effect sizes in all cognitive measures. In the full study sample and/or the combined patient/relative groups, higher BDI scores were associated with increased response latency, and higher ASRM scores with increased response bias and false alarms (Po0.05). In the patient sample, PANSS negative symptoms were associated with reduced response bias and increased false alarms (Po0.05). GL scores did not correlate significantly with any RVIP measure (P40.10).
4. Discussion This is the first study to examine sustained attention in nonbipolar, non-psychotic relatives of patients with psychotic BD-I from multiplex families. The index cases showed SA deficits which were statistically significant compared to their relatives, but yielded small effect sizes compared to the controls. The relatives did not differ from controls in any SA measure. These findings were not due to confounding effects of IQ, persisted after excluding relatives/controls with psychiatric diagnoses, and contradicted our hypotheses. Extending this result, SA failed to show significant correlations with a continuous measure of genetic loading on psychosis. Our results indicate that sustained attention is an unlikely endophenotype for psychotic BD-I, since a core criterion for endophenotypes, i.e. presence in unaffected relatives (Gottesman
and Gould, 2003), was not satisfied in the present study, despite sampling patients with a form of BD-I (psychotic and familial) with increased homogeneity, clinical severity and presumed genetic and neuropsychological overlap with schizophrenia. Our findings further suggest that the preponderance of negative findings in the few relevant studies of unaffected relatives (Bora et al., 2008; Clark et al., 2005; Ferrier et al., 2004; Frantom et al., 2008; Glahn et al., 2010; Jabben et al., 2009; Kieseppa et al., 2005; Kumar et al., 2010) is unlikely to be an artefact of small or heterogeneous samples, or of the low discriminability of cognitive deficits in BD compared to schizophrenia (Krabbendam et al., 2005). Our findings are also in line with the absence of selective attention deficits (another candidate attentional endophenotype for BD-I) in a largely overlapping sample of first-degree relatives of BD-I patients reported on previously by our group (Kravariti et al., 2009; for other neurocognitive findings from this sample see Schulze et al. (2011)). Our broad source of patient ascertainment included both clinical and community settings. Therefore, we cannot exclude the possibility that a familial risk for SA deficits is confined to a subgroup of patients who are more likely to be found among in/out-patient cohorts. We conclude that being a first-degree relative of an individual with a severe form of bipolar I disorder with psychotic features, indexed from families multiply affected with psychosis, does not confer risk for sustained attention deficits. However, earlier findings of SA deficits in unaffected relatives of BD patients by a small number of studies (Kremen et al., 1998; Klimes-Dougan et al., 2006; Trivedi et al., 2008; Bora et al., 2009) suggest that further research is needed to clarify the endophenotypic potential of SA deficits in bipolar disorder.
Acknowledgements MW and EK received funding support from the Psychiatry Research Trust. The work was funded by Guy’s and St. Thomas’ Charitable Foundation Research Studentship to KS. We would like to thank the Manic Depression Fellowship for help with recruitment of participants and also all the families who took part in this research.
References Altman, E.G., Hedeker, D., Peterson, J.L., Davis, J.M., 1997. The Altman self-rating mania scale. Biological Psychiatry 42, 948–955. Beck, A., Ward, C., Mendelson, M., Mock, J., Erbaugh, J., 1961. An inventory for measuring depression. Archives of General Psychiatry 4, 561–571. Bora, E., Yucel, M., Pantelis, C., 2009. Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. Journal of Affective Disorders 113, 1–20. Bora, E., Vahip, S., Akdeniz, F., Ilerisoy, H., Aldemir, E., Alkan, M., 2008. Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder. Psychiatry Research 161, 318–324. Cambridge Cognition, 2006. Cambridge Neuropsychological Test Automated Battery (CANTAB). Chen, W., Faraone, S., 2000. Sustained attention deficits as markers of genetic susceptibility to schizophrenia. American Journal of Medical Genetics 97, 52–57. Clark, L., Kempton, M., Scarna , A., Grasby, P., Goodwin, G., 2005. Sustained attention-deficit confirmed in euthymic bipolar disorder but not in firstdegree relatives of bipolar patients or euthymic unipolar depression. Biological Psychiatry 57, 183–187. Cornblatt, B., Malhotra, A., 2001. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. American Journal of Medical Genetics 105, 11–15. Ferrier, I., Chowdhury, R., Thompson, J., Watson, S., Young, A., 2004. Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disorders 6, 319–322. Frantom, L., Allen, D., Cross, C., 2008. Neurocognitive endophenotypes for bipolar disorder. Bipolar Disorders 10, 387–399.
M. Walshe et al. / Psychiatry Research 199 (2012) 70–73
Glahn, D.C., Almasy, L., Barguil, M., Hare, E., Peralta, J.M., Kent Jr, J.W., Dassori, A., Contreras, J., Pacheco, A., Lanzagorta, N., Nicolini, H., Raventos, H., Escamilla, M.A., 2010. Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families. Archives of General Psychiatry 67, 168–177. Godard, J., Grondin, S., Baruch, P., Lafleur, M.F., 2011. Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder. Psychiatry Research 190, 244–252. Gottesman, I., Gould, T., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636–645. Jabben, N., Arts, B., Krabbendam, L., Van Os, J., 2009. Investigating the association between neurocognition and psychosis in bipolar disorder: further evidence for the overlap with schizophrenia. Bipolar Disorders 11, 166–177. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276. Kieseppa, T., Tuulio-Henriksson, A., Haukka, J., Van Erp, T., Glahn, D., Cannon, T., Partonen, T., Kaprio, J., Lonnqvist, J., 2005. Memory and verbal learning functions in twins with bipolar-I disorder, and the role of informationprocessing speed. Psychological Medicine 35, 205–215. Klimes-Dougan, B., Ronsaville, D., Wiggs, E.A., Martinez, P.E., 2006. Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders. Biological Psychiatry 60, 957–965. Krabbendam, L., Arts, B., van Os, J., Aleman, A., 2005. Cognitive functioning in patients with schizophrenia and bipolar disorder: a quantitative review. Schizophrenia Research 80, 137–149. Kravariti, E., Dixon, T., Frith, C., Murray, R.M., McGuire, P., 2005. Association of symptoms and executive function in schizophrenia and bipolar disorder. Schizophrenia Research 74, 221–231. Kravariti, E., Schulze, K., Kane, F., Kalidindi, S., Bramon, E., Walshe, M., Marshall, N., Hall, M.H., Georgiades, A., McDonald, C., Murray, R.M., 2009. Stroop-test interference in bipolar disorder. British Journal of Psychiatry 194, 285–286. Kremen, W., Faraone, S., Seidman, L., Pepple, J., Tsuang, M., 1998. Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands. Psychiatry Research 79, 227–240. Kumar, C.T.S., Christodoulou, T., Vyas, N.S., Kyriakopoulos, M., Corrigall, R., Reichenberg, A., Frangou, S., 2010. Deficits in visual sustained attention differentiate genetic liability and disease expression for Schizophrenia from bipolar disorder. Schizophrenia Research 124, 152–160. McDonald, C., Bullmore, E., Sham, P., Chitnis, X., Wickham, H., Bramon, E., Murray, R.M., 2004. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Archives of General Psychiatry 61, 974–984.
73
Murray, R.M., Sham, P., van Os, J., Zanelli, J., Cannon, M., McDonald, C., 2004. A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophrenia Research 71, 405–416. Nurnberger, J.I., Blehar, M.C., Kaufmann, C.A., York-Cooler, C., Simpson, S.G., Harkavy-Friedman, J., Severe, J.B., Malaspina, D., Reich, T., 1994. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Archives of General Psychiatry 51, 849–859. Schulze, K., Walshe, M., Stahl, D., Kravariti, E., Morris, R.G., Marshall, N., Hall, M.-H., Murray, R.M., Bramon, E., 2011. Executive functioning in familial bipolar I disorder patients and their unaffected relatives. Bipolar Disorders 13, 208–216. Simonsen, C., Sundet, K., Vaskinn, A., Birkenaes, A., Engh, J., Faerden, A., Jonsdottir, H., Ringen, P., Opjordsmoen, S., Melle, I., Friis, S., Andreassen, O., 2011. Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophrenia Bulletin 37, 73–83. Spitzer, R., Endicott, J., 1978. Schedule for Affective Disorders and SchizophreniaLifetime Version. New York State Psychiatric Institute, New York. StataCorp, 2007. STATA v.10.0 for Windows. The International Schizophrenia Consortium, 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752. Trivedi, J., Goel, D., Dhyani, M., Sharma, S., Singh, A., Sinha, P.R.T., 2008. Neurocognition in first-degree healthy relatives (siblings) of bipolar affective disorder patients. Psychiatry and Clinical Neurosciences 62, 190–196. Tsuang, H., Lin, S., Liu, S., Hsieh, M., Hwang, T., Liu, C., Hwu, H., Chen, W., 2006. More severe sustained attention deficits in nonpsychotic siblings of multiplex schizophrenia families than in those of simplex ones. Schizophrenia Research 87, 172–180. Wang, Q., Chan, R., Sun, J., Yao, J., Deng, W., Sun, X., Liu, X., Sham, P., Ma, X., Meng, H., Murray, R.M., Collier, D., Li, T., 2007. Reaction time of the continuous performance test is an endophenotypic marker for schizophrenia: a study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls. Schizophrenia Research 89, 293–298. Wechsler, D., 1999. Wechsler abbreviated scale of intelligence (WASI). The Psychological Corporation. Williams, R., 2000. A note on robust variance estimation for cluster-correlated data. Biometrics 56, 645–646. Winter, K., Stone, A., Weintraub, S., Neale, J., 1981. Cognitive and attentional deficits in children vulnerable to psychopathology. Journal of Abnormal Child Psychology 9, 435–453.