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 abnor-
malities—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
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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 voxel-
based 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: hr18@nyu.edu)
1 Harrison PJ. Brains at risk of schizophrenia. Lancet 1999; 353: 3–4.
2 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.
3 McCarley RW, Wible CG, Frumin M, et al. MRI anatomy of
schizophrenia. Biol Psychiat 1999; 45: 1099–119.
4 Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of
MRI findings in schizophrenia. Schizophren Res 2001; 49: 1–52.
5 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.
6 Woodruff PW, McManus IC, David AS. Meta-analysis of corpus
callosum size in schizophrenia. J Neurol Neurosurg Psychiat 1995; 58:
457–61.
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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 two-
parent 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
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COMMENTARY
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: mmw@liverpool.ac.uk)
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.
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