- Email: [email protected]
A neuropathology of psychosis?
COMMENTARY
COMMENTARY
A neuropathology of psychosis? See page 281 Published online Dec 10, 2002 http://image.thelancet.com/extras/02cmt238web.pdf
In a 1999 Lancet Commentary1 on an article2 describing brain findings on magnetic-resonance imaging in individuals at high risk for schizophrenia, Harrison noted: “the question is no longer ‘Is schizophrenia a brain disease?’ but ‘What sort of disease is it? . . . When do the changes occur?’” Three years later with continued intense scrutiny, structural study in the central nervous system in schizophrenia remains confoundingly complex. Evidence of temporal lobe abnormalities, particularly in mesial structures, has been convincingly replicated,3 including at the onset of schizophrenic symptoms4 and in individuals at increased genetic risk2 for schizophrenia. In addition, there is evidence of more widespread brain abnormalities, including in prefrontal lobe grey3 and white matter,5 in the corpus callosum,6 and—the most replicated finding— ventricular enlargement.7 Indeed, in-utero ultrasonography has even demonstrated enlarged ventricles in high-risk fetuses.8 Questions still largely unanswered concern the time course and pathophysiological basis of these abnormalities—at what point in neurodevelopment and in relation to nascent schizophrenic disease manifestation do central nervous system deviations emerge and what is the basis for the inter-individual variability in distribution of grey and white matter lesions? The study in today’s Lancet by C Pantelis and colleagues reports on a crucial slice in time among individuals with psychotic illness: the transition from prodromal to frank psychosis. The investigators note diminished grey matter in right medial and lateral temporal areas, in the right inferior frontal cortex, and throughout the cingulate in subjects at high risk for psychosis who subsequently became ill. They suggest that these abnormalities may be a signature of psychoses. The individuals who developed psychoses were diagnostically heterogeneous, with an approximately even mix of schizophrenic and affective diagnoses. Whether the anatomic deficits represent a core neuropathology of psychoses or simply a conglomeration of lesions reflecting the diagnostic heterogeneity of this sample is a fascinating question that will require further study. One obvious implication for these findings concerns evidence that early treatment of schizophrenia before the onset of symptoms may alter the course of the disease.9 The delineation by magnetic-resonance imaging of a structural profile present before the onset of psychosis could provide a more robust basis on which antipsychotic medication could be started with a reasonable risk-benefit ratio. A subset of the patients (n=10) with psychotic illnesses for whom follow-up scans were obtained showed ongoing reduction in cingulate grey matter, as well as more 270
prominent left hemispheric grey matter abnormalities in the parahippocampal, fusiform, orbitofrontal, and cerebellar cortex. These abnormalities may have already been present before onset of symptoms, but the study lacked sufficient power to detect them in the baseline across-subject comparison. Nonetheless, the suggestion that the onset of psychosis may represent a critical inflection point in the unfolding of brain pathology is an intriguing and novel aspect of this report. High-resolution magnetic-resonance imaging facilitates cross-sectional and longitudinal morphometric analyses of the human brain in vivo, in a large number of individuals. Manual tracing of individual gyri on the original images is labour intensive. Automated methods, such as the voxelbased morphometry used by Pantelis and colleagues, allow whole-brain statistical analyses with little user-interaction. Voxel-based morphometry also allows identification of changes within highly localised regions. The investigators used this complex technique carefully: images of study participants were used to construct the template in Talairach space and random permutation tests established the statistical significance of clusters of voxels that represent the sites of grey-matter loss. Although neuroimaging reports based on automated methods are accumulating, such methods are still in their early stage of development. Whilst significant results usually indicate systematic differences in grey matter, they may also represent spatial misregistration or differences in T1 contrast.10 There is a highly significant relation between T1 relaxation time and age in cerebral grey and white matter of normal individuals under the age of 35.11 Moreover, there are recent instances of the methodological discrepancy between voxel-based morphometry and expert manual delineation.12 The importance of the hypothesis relating frank psychosis with regional loss of cortical volume merits further confirmation using more direct observations. Adam Wolkin, *Henry Rusinek Mental Health Service, VA New York Harbor Healthcare System, New York (AW); and Departments of Psychiatry (AW) and *Radiology (HR), New York University School of Medicine, New York, NY 10016, USA (e-mail: [email protected]) 1 2
3 4 5
6
Harrison PJ. Brains at risk of schizophrenia. Lancet 1999; 353: 3–4. Lawrie SM, Whalley H, Kestelman JN, et al. Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 1999; 353: 30–33. McCarley RW, Wible CG, Frumin M, et al. MRI anatomy of schizophrenia. Biol Psychiat 1999; 45: 1099–119. Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophren Res 2001; 49: 1–52. Sanfilipo M, Lafargue T, Rusinek H, et al. Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch Gen Psychiat 2000; 57: 471–80. Woodruff PW, McManus IC, David AS. Meta-analysis of corpus callosum size in schizophrenia. J Neurol Neurosurg Psychiat 1995; 58: 457–61.
THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
7
Sanfilipo M, Lafargue T, Arena L, et al. Fine volumetric analysis of the cerebral ventricular system in schizophrenia: further evidence for multifocal mild to moderate enlargement. Schizophren Bull 2000; 26: 201–16. 8 Gilmore JH, van Tol JJ, Lewis SH, et al. Outcome in children with fetal mild ventriculomegaly: a case series. Schizophr Res 2001; 48: 219–26. 9 Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiat 2001; 50: 884–97. 10 Ashburner J, Friston KJ. Why voxel-based morphometry should be used. Neuroimage 2001; 14: 1238–43. 11 Cho S, Jones D, Reddick WE, Ogg RJ, Steen RG. Establishing norms for age-related changes in proton T1 of human brain tissue in vivo. Magnetic Reson Imag 1997; 15: 1133–43. 12 Tisserand DJ, Pruessner JC, Sanz Argita EJ, et al. Regional frontal cortical volumes decrease differentially in aging: a MRI study to compare volumetric approaches and voxel-based morphometry. Neuroimage 2002; 17: 657–69.
What puts children of lone parents at a health disadvantage? See page 289 The health disadvantage of lone mothers in industrialised countries has raised questions about the health of the children who live with them.1–5 Few studies, however, have analysed the health of children living with lone, compared with two parents, with sufficient sociodemographic data to adjust for key confounding and mediating factors. The paper in today’s Lancet by Gunilla Ringbäck Weitoft and colleagues is, therefore, important, not least because it is longitudinal, achieves almost complete population coverage, and links national registers to attach extensive socioeconomic data to health outcomes. The investigators followed up the mortality, severe morbidity, and hospital inpatient use of nearly a million Swedish children over 9 years. The main findings are that, after controlling for confounders, Swedish children of lone parents have more than double the risk of psychiatric disease, suicide or attempted suicide, and alcohol-related disease; and more than three times the risk of drug-related disease compared with their counterparts in two-parent households. Boys in lone-parent families also had increased risk of all-cause mortality. The question is what causes this health disadvantage? The investigators test various explanatory hypotheses and conclude that lack of household resources, as measured by receipt of social benefit and renting rather than owning a home, has a major role in accounting for these increased risks. The findings still leave major questions about why and how. What are the causal pathways, for instance, by which inequalities in household resources could translate into differential risk to health for lone-parent versus twoparent households? And are these pathways necessarily the same in different countries? The possibility of different social pathways to ill-health in contrasting policy contexts has recently been raised by the findings of cross-country comparisons. Take, for example, the hypothesised pathway that financial hardship of lone parents causes heightened anxiety, depression, and social isolation, which in turn leads not only to psychiatric disease but also to strategies for coping with hardship which include excess use of tobacco and other health-damaging substances. Evidence to support these psychological and social mechanisms has been found in relation to lone mothers in the UK.6–9 Most Swedish lone-parent households, however, cannot be considered to be in financial hardship in the same sense that their UK counterparts are, even in relative terms. In a THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
study comparing Britain and Sweden, less than 10% of Swedish lone-mothers were poor (measured as below 50% of median income, standardised for family size). Most were working, but even among those who were not, only a few were classed as poor by this measure.1,4 The Swedish welfare system largely protected lone mothers from poverty and unemployment, in stark contrast with the UK situation, in which most lone mothers were still poor, even with the help of welfare benefits. Under these conditions, poverty and worklessness, in subsequent analyses, explained much of the health disadvantage of lone mothers compared with couple mothers in Britain but little or nothing of the equivalent health gap in Sweden.4 The search continues for what it is about the economic and social experiences of lone parents in Sweden that is ultimately damaging to their own health and that of their children. What such studies highlight more generally is the need for a deeper understanding of the policy context in the various societies under study, and the need to question the meaning of what is being measured. Part of the issue may be that the necessarily crude indicators used to measure complex sociological processes may have different meanings in different places. Whilst in the UK and USA, receipt of welfare benefits is often taken as a marker of poverty, what is this variable capturing in Sweden in Ringbäck Weitoft and colleagues’ study? The same question applies to the housing-tenure indicator of renting versus owning a home. In some contexts, housing tenure indicates more than the level of income alone, encompassing notions of degree of control over available resources and perceptions of longer-term security.10,11 Future studies need to take these lines of investigation forward, to increase understanding of the subtleties of the multiple pathways to health disadvantage in specific societies. Such work is imperative to find effective policies, matched to prevailing circumstances, to address these inequalities. *Margaret Whitehead, Paula Holland Department of Public Health, University of Liverpool, Liverpool L69 3GB, UK (e-mail: [email protected]) 1
Burström B, Diderichsen F, Shouls S, Whitehead M. Lone mothers in Sweden: trends in health and socio-economic circumstances, 1979–1995. J Epidemiol Community Health 1999: 53: 750–56. 2 Whitehead M, Drever F. Narrowing inequalities in health? Analysis of trends in mortality among the babies of lone mothers. BMJ 1999; 318: 908–14. 3 Ringbäck Weitoft G, Haglund B, Rosen M. Mortality among lone mothers in Sweden: a population study. Lancet 2000; 355: 1215–19. 4 Whitehead M, Burström B, Diderichsen F. Social policies and the pathways to inequalities in health: a comparative analysis of lone mothers in Britain and Sweden. Soc Sci Med 2000, 50: 255–70. 5 Lahelma E, Arber S, Kivelä K, Roos E. Multiple roles and health among British and Finnish women: the influence of socio-economic circumstances. Soc Sci Med 2002; 54: 727–40. 6 Brown G, Moran P. Single mothers, poverty and depression. Psychol Med 1997; 27: 21–33. 7 Hope S, Power C, Rodgers B. Does financial hardship account for elevated psychological distress in lone mothers? Soc Sci Med 1999; 49: 1637–49. 8 Graham H. Being poor: perceptions and coping strategies of lone mothers. In: Brannen J, Wilson G, eds. Give and take in families: studies on resource distribution. London: Allen and Unwin, 1987: 56–74. 9 Graham H. Women’s smoking and family health. Soc Sci Med 1987; 25: 47–56. 10 Macintyre S, Ellaway A, Der G, Ford G, Hunt K. Are housing tenure and car access simply measures of income or self-esteem? A Scottish study. J Epidemiol Community Health 1998; 52: 657–64. 11 Hiscock R, Kearns A, Macintyre S, Ellaway A. Ontological security and psychosocial benefits from the home: qualitative evidence on issues of tenure. Housing Theory Soc 2001; 18: 50–66.
271
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
A neuropathology of psychosis? See page 281 Published online Dec 10, 2002 http://image.thelancet.com/extras/02cmt238web.pdf
In a 1999 Lancet Commentary1 on an article2 describing brain findings on magnetic-resonance imaging in individuals at high risk for schizophrenia, Harrison noted: “the question is no longer ‘Is schizophrenia a brain disease?’ but ‘What sort of disease is it? . . . When do the changes occur?’” Three years later with continued intense scrutiny, structural study in the central nervous system in schizophrenia remains confoundingly complex. Evidence of temporal lobe abnormalities, particularly in mesial structures, has been convincingly replicated,3 including at the onset of schizophrenic symptoms4 and in individuals at increased genetic risk2 for schizophrenia. In addition, there is evidence of more widespread brain abnormalities, including in prefrontal lobe grey3 and white matter,5 in the corpus callosum,6 and—the most replicated finding— ventricular enlargement.7 Indeed, in-utero ultrasonography has even demonstrated enlarged ventricles in high-risk fetuses.8 Questions still largely unanswered concern the time course and pathophysiological basis of these abnormalities—at what point in neurodevelopment and in relation to nascent schizophrenic disease manifestation do central nervous system deviations emerge and what is the basis for the inter-individual variability in distribution of grey and white matter lesions? The study in today’s Lancet by C Pantelis and colleagues reports on a crucial slice in time among individuals with psychotic illness: the transition from prodromal to frank psychosis. The investigators note diminished grey matter in right medial and lateral temporal areas, in the right inferior frontal cortex, and throughout the cingulate in subjects at high risk for psychosis who subsequently became ill. They suggest that these abnormalities may be a signature of psychoses. The individuals who developed psychoses were diagnostically heterogeneous, with an approximately even mix of schizophrenic and affective diagnoses. Whether the anatomic deficits represent a core neuropathology of psychoses or simply a conglomeration of lesions reflecting the diagnostic heterogeneity of this sample is a fascinating question that will require further study. One obvious implication for these findings concerns evidence that early treatment of schizophrenia before the onset of symptoms may alter the course of the disease.9 The delineation by magnetic-resonance imaging of a structural profile present before the onset of psychosis could provide a more robust basis on which antipsychotic medication could be started with a reasonable risk-benefit ratio. A subset of the patients (n=10) with psychotic illnesses for whom follow-up scans were obtained showed ongoing reduction in cingulate grey matter, as well as more 270
prominent left hemispheric grey matter abnormalities in the parahippocampal, fusiform, orbitofrontal, and cerebellar cortex. These abnormalities may have already been present before onset of symptoms, but the study lacked sufficient power to detect them in the baseline across-subject comparison. Nonetheless, the suggestion that the onset of psychosis may represent a critical inflection point in the unfolding of brain pathology is an intriguing and novel aspect of this report. High-resolution magnetic-resonance imaging facilitates cross-sectional and longitudinal morphometric analyses of the human brain in vivo, in a large number of individuals. Manual tracing of individual gyri on the original images is labour intensive. Automated methods, such as the voxelbased morphometry used by Pantelis and colleagues, allow whole-brain statistical analyses with little user-interaction. Voxel-based morphometry also allows identification of changes within highly localised regions. The investigators used this complex technique carefully: images of study participants were used to construct the template in Talairach space and random permutation tests established the statistical significance of clusters of voxels that represent the sites of grey-matter loss. Although neuroimaging reports based on automated methods are accumulating, such methods are still in their early stage of development. Whilst significant results usually indicate systematic differences in grey matter, they may also represent spatial misregistration or differences in T1 contrast.10 There is a highly significant relation between T1 relaxation time and age in cerebral grey and white matter of normal individuals under the age of 35.11 Moreover, there are recent instances of the methodological discrepancy between voxel-based morphometry and expert manual delineation.12 The importance of the hypothesis relating frank psychosis with regional loss of cortical volume merits further confirmation using more direct observations. Adam Wolkin, *Henry Rusinek Mental Health Service, VA New York Harbor Healthcare System, New York (AW); and Departments of Psychiatry (AW) and *Radiology (HR), New York University School of Medicine, New York, NY 10016, USA (e-mail: [email protected]) 1 2
3 4 5
6
Harrison PJ. Brains at risk of schizophrenia. Lancet 1999; 353: 3–4. Lawrie SM, Whalley H, Kestelman JN, et al. Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 1999; 353: 30–33. McCarley RW, Wible CG, Frumin M, et al. MRI anatomy of schizophrenia. Biol Psychiat 1999; 45: 1099–119. Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophren Res 2001; 49: 1–52. Sanfilipo M, Lafargue T, Rusinek H, et al. Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch Gen Psychiat 2000; 57: 471–80. Woodruff PW, McManus IC, David AS. Meta-analysis of corpus callosum size in schizophrenia. J Neurol Neurosurg Psychiat 1995; 58: 457–61.
THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
7
Sanfilipo M, Lafargue T, Arena L, et al. Fine volumetric analysis of the cerebral ventricular system in schizophrenia: further evidence for multifocal mild to moderate enlargement. Schizophren Bull 2000; 26: 201–16. 8 Gilmore JH, van Tol JJ, Lewis SH, et al. Outcome in children with fetal mild ventriculomegaly: a case series. Schizophr Res 2001; 48: 219–26. 9 Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiat 2001; 50: 884–97. 10 Ashburner J, Friston KJ. Why voxel-based morphometry should be used. Neuroimage 2001; 14: 1238–43. 11 Cho S, Jones D, Reddick WE, Ogg RJ, Steen RG. Establishing norms for age-related changes in proton T1 of human brain tissue in vivo. Magnetic Reson Imag 1997; 15: 1133–43. 12 Tisserand DJ, Pruessner JC, Sanz Argita EJ, et al. Regional frontal cortical volumes decrease differentially in aging: a MRI study to compare volumetric approaches and voxel-based morphometry. Neuroimage 2002; 17: 657–69.
What puts children of lone parents at a health disadvantage? See page 289 The health disadvantage of lone mothers in industrialised countries has raised questions about the health of the children who live with them.1–5 Few studies, however, have analysed the health of children living with lone, compared with two parents, with sufficient sociodemographic data to adjust for key confounding and mediating factors. The paper in today’s Lancet by Gunilla Ringbäck Weitoft and colleagues is, therefore, important, not least because it is longitudinal, achieves almost complete population coverage, and links national registers to attach extensive socioeconomic data to health outcomes. The investigators followed up the mortality, severe morbidity, and hospital inpatient use of nearly a million Swedish children over 9 years. The main findings are that, after controlling for confounders, Swedish children of lone parents have more than double the risk of psychiatric disease, suicide or attempted suicide, and alcohol-related disease; and more than three times the risk of drug-related disease compared with their counterparts in two-parent households. Boys in lone-parent families also had increased risk of all-cause mortality. The question is what causes this health disadvantage? The investigators test various explanatory hypotheses and conclude that lack of household resources, as measured by receipt of social benefit and renting rather than owning a home, has a major role in accounting for these increased risks. The findings still leave major questions about why and how. What are the causal pathways, for instance, by which inequalities in household resources could translate into differential risk to health for lone-parent versus twoparent households? And are these pathways necessarily the same in different countries? The possibility of different social pathways to ill-health in contrasting policy contexts has recently been raised by the findings of cross-country comparisons. Take, for example, the hypothesised pathway that financial hardship of lone parents causes heightened anxiety, depression, and social isolation, which in turn leads not only to psychiatric disease but also to strategies for coping with hardship which include excess use of tobacco and other health-damaging substances. Evidence to support these psychological and social mechanisms has been found in relation to lone mothers in the UK.6–9 Most Swedish lone-parent households, however, cannot be considered to be in financial hardship in the same sense that their UK counterparts are, even in relative terms. In a THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
study comparing Britain and Sweden, less than 10% of Swedish lone-mothers were poor (measured as below 50% of median income, standardised for family size). Most were working, but even among those who were not, only a few were classed as poor by this measure.1,4 The Swedish welfare system largely protected lone mothers from poverty and unemployment, in stark contrast with the UK situation, in which most lone mothers were still poor, even with the help of welfare benefits. Under these conditions, poverty and worklessness, in subsequent analyses, explained much of the health disadvantage of lone mothers compared with couple mothers in Britain but little or nothing of the equivalent health gap in Sweden.4 The search continues for what it is about the economic and social experiences of lone parents in Sweden that is ultimately damaging to their own health and that of their children. What such studies highlight more generally is the need for a deeper understanding of the policy context in the various societies under study, and the need to question the meaning of what is being measured. Part of the issue may be that the necessarily crude indicators used to measure complex sociological processes may have different meanings in different places. Whilst in the UK and USA, receipt of welfare benefits is often taken as a marker of poverty, what is this variable capturing in Sweden in Ringbäck Weitoft and colleagues’ study? The same question applies to the housing-tenure indicator of renting versus owning a home. In some contexts, housing tenure indicates more than the level of income alone, encompassing notions of degree of control over available resources and perceptions of longer-term security.10,11 Future studies need to take these lines of investigation forward, to increase understanding of the subtleties of the multiple pathways to health disadvantage in specific societies. Such work is imperative to find effective policies, matched to prevailing circumstances, to address these inequalities. *Margaret Whitehead, Paula Holland Department of Public Health, University of Liverpool, Liverpool L69 3GB, UK (e-mail: [email protected]) 1
Burström B, Diderichsen F, Shouls S, Whitehead M. Lone mothers in Sweden: trends in health and socio-economic circumstances, 1979–1995. J Epidemiol Community Health 1999: 53: 750–56. 2 Whitehead M, Drever F. Narrowing inequalities in health? Analysis of trends in mortality among the babies of lone mothers. BMJ 1999; 318: 908–14. 3 Ringbäck Weitoft G, Haglund B, Rosen M. Mortality among lone mothers in Sweden: a population study. Lancet 2000; 355: 1215–19. 4 Whitehead M, Burström B, Diderichsen F. Social policies and the pathways to inequalities in health: a comparative analysis of lone mothers in Britain and Sweden. Soc Sci Med 2000, 50: 255–70. 5 Lahelma E, Arber S, Kivelä K, Roos E. Multiple roles and health among British and Finnish women: the influence of socio-economic circumstances. Soc Sci Med 2002; 54: 727–40. 6 Brown G, Moran P. Single mothers, poverty and depression. Psychol Med 1997; 27: 21–33. 7 Hope S, Power C, Rodgers B. Does financial hardship account for elevated psychological distress in lone mothers? Soc Sci Med 1999; 49: 1637–49. 8 Graham H. Being poor: perceptions and coping strategies of lone mothers. In: Brannen J, Wilson G, eds. Give and take in families: studies on resource distribution. London: Allen and Unwin, 1987: 56–74. 9 Graham H. Women’s smoking and family health. Soc Sci Med 1987; 25: 47–56. 10 Macintyre S, Ellaway A, Der G, Ford G, Hunt K. Are housing tenure and car access simply measures of income or self-esteem? A Scottish study. J Epidemiol Community Health 1998; 52: 657–64. 11 Hiscock R, Kearns A, Macintyre S, Ellaway A. Ontological security and psychosocial benefits from the home: qualitative evidence on issues of tenure. Housing Theory Soc 2001; 18: 50–66.
271
For personal use. Only reproduce with permission from The Lancet Publishing Group.