Schizophrenia Research 86 (2006) 45 – 53
Evidence that brain tissue volumes are associated with HVA
reactivity to metabolic stress in schizophrenia
Machteld Marcelis a,⁎, John Suckling b , Paul Hofman c , Peter Woodruff d ,
Ed Bullmore e , Jim van Os a,f
Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University,
PO Box 616 (VIJV1), 6200 MD Maastricht, The Netherlands
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
Department of Radiology, University Hospital Maastricht, Maastricht, The Netherlands
Department of Psychiatry, Sheffield Cognition and Neuroimaging Laboratory, Academic Clinical Psychiatry, University of Sheffield,
The Longley Centre, Norwood Grange Drive, Sheffield, S5 7JT, UK
Department of Psychiatry, University of Cambridge, UK
Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK
Received 27 July 2005; received in revised form 1 May 2006; accepted 2 May 2006
Available online 27 June 2006
Background: Although liability to psychosis is thought to have its origins in cerebral alterations, expressed as cerebral grey and
white matter loss, less is known about the degree to which such vulnerabilities impact on functional parameters, in particular altered
stress reactivity. Breier et al. [Breier, A., Davis, O.R., Buchanan, R.W., Moricle, L.A., Munson, R.C., 1993b. Effects of metabolic
perturbation on plasma homovanillic acid in schizophrenia. Relationship to prefrontal cortex volume. Arch. Gen. Psychiatry 50(7),
541–550] reported that lower prefrontal cortex volume was associated with altered metabolic stress response, but this finding has
never been replicated.
Methods: Thirty-one patients with psychosis underwent structural magnetic resonance imaging scanning and a metabolic stress
paradigm (glucoprivic 2-deoxyglucose (2DG) condition versus placebo condition) that yielded information on plasma
homovanillic acid (HVA) reactivity. Total cerebral tissue volumes were derived from automated segmentation procedures.
Associations between metabolic stress and tissue volumes (as well as their interactions) on the one hand, and plasma HVA level on
the other, were investigated using multilevel random regression techniques.
Results: Analysis revealed a significant increase in plasma HVA over time in the 2DG condition. The increase in HVA in the stress
condition was stronger in patients with lower grey and white matter volumes. There was no significant interaction between
metabolic stress and CSF volume.
Conclusion: Lower grey and white matter volumes in schizophrenia are associated with a dysregulated dopaminergic/noradrenergic
mediated stress response. These findings may support the hypothesis that alterations in cortico-subcortical connections affect
psychosis susceptibility through an altered stress response.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Schizophrenia; Brain alteration; Magnetic resonance imaging; Metabolic stress; Homovanillic acid; Dopamine
⁎ Corresponding author. Tel.: +31 43 3688679/666; fax: +31 43 3688689.
E-mail address: email@example.com (M. Marcelis).
0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
46 M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53
1. Introduction with patients showing an increased dopamine (DA)/
noradrenaline (NA) response compared to controls
The liability to schizophrenia is thought to have its (Marcelis et al., 2004). The aim of the present inves-
origins in cerebral alterations, expressed as structural tigation was to independently replicate the earlier
abnormalities such as reductions in total brain volume, findings of a relationship between brain tissue and the
and grey and white matter volume (Wright et al., 2000). HVA response to metabolic stress (Breier et al., 1993b),
However, very little is known about how such but now in a much larger sample.
vulnerabilities impact on functional measures, in partic- We hypothesized that functional cerebral vulnerabil-
ular the response to stress. ity, conceptualized in terms of heightened DA/NA
The altered stress response in schizophrenia is responsivity during 2DG perturbation is associated with
thought to be associated with the process of dopamine changes in brain structure in psychosis. Increasing
sensitization, referring to hyperresponsiveness of DA evidence indicates that temporolimbic–prefrontal dys-
neurons to environmental stimuli, in which exposure to function in schizophrenia is associated with enhanced
even moderate levels of stress are associated with an subcortical dopamine release (Heinz et al., 2003).
excessive DA response (Davis et al., 1991; Glenthoj, Alterations in the capacity of a stress buffering system,
1995; Laruelle, 2000; Laruelle and Abi-Dargham, such as prefrontal dopaminergic function, may result
1999). In schizophrenia, a dysregulated, hyperdopami- from aberrant development of cortical cytoarchitecture
nergic state may lead to stimulus-independent release of (Weinberger and Lipka, 1995). During mild stress,
dopamine and to aberrant assignment of salience to dopamine release and metabolism is preferentially
experiences, which may serve as a framework for the increased in the mesocortical system, compared to the
emergence of psychotic symptoms (Kapur, 2003). mesolimbic and nigrostriatal systems. This increase in
An experimental paradigm to examine perturbation prefrontal dopamine following mild stress is thought to
on dopamine function following stress exposure inhibit subcortical dopamine transmission, thereby
involves glucose deprivation by intravenous infusion providing protection against positive symptoms (Deutch
of 2-deoxyglucose (2DG) (Breier, 1989; Breier et al., et al., 1990; Vermetten and Bremner, 2002). By
1992b; Mitropoulou et al., 2004). The glucose-analog impacting negatively on mesocortical dopamine func-
2DG causes glucoprivation by competing with glucose- tion, reduced cortical volume in schizophrenia may thus
6-phospate during the early stage of glycolysis and affect the stress-buffering system and lead to increases
inhibits intracellular glucose utilization. As glucose is in subcortical dopamine activity following even mild
the primary energy source for the central nervous stressors (Laruelle, 2000).
system, disruption of glucose metabolism is a potent Dysfunctional connections between the cortex and
CNS stressor. This metabolic stress paradigm has been the midbrain may be reflected by white matter
found to produce robust activation of the hypothalamic– reduction. We tested whether reduced cerebral grey
pituitary–adrenal (HPA) axis, as well as elevations of and white matter is associated with an increased DA/
epinephrine and of behavioral (stress/anxiety) and NA-mediated stress response following 2DG-adminis-
physiologic (heart rate/blood pressure) measures (Breier tration in patients with psychosis.
et al., 1992b; Elman et al., 1999). Moreover, it strongly
affects central and peripheral dopamine function, as well 2. Methods
as the plasma levels of homovanillic acid (HVA), a
breakdown product of dopamine as well as noradren- 2.1. Study sample
aline. Plasma HVA, although largely derived from the
periphery, is thought to reflect, at least partly, the central The patient sample is part of the Maastricht
dopamine response to stress (Breier, 1989; Breier et al., Psychosis Study (Marcelis et al., 2003a,b, 2004). MRI
1993b). and HVA data were available for 31 out of 50 patients
Measuring plasma HVA repetitively during metabolic with psychosis.
stress, Breier et al. (1993b) not only found that patients Patients between 16 and 55 years with a life-time
with schizophrenia had significantly greater 2DG- history of psychosis according to the RDC criteria
induced plasma HVA elevations as compared to controls, (Spitzer et al., 1978), who were not currently in need of
but also that these elevations in HVA levels were in-patient treatment, intensive case management home
associated with lower prefrontal cortex volumes. In a care, or case management crisis intervention, were
recent study using the same paradigm, this finding of recruited at the community mental health center in
altered stress response in schizophrenia was replicated, Maastricht, the Netherlands.
M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53 47
Other inclusion criteria included being in good was generated from linear scale-space features derived
health, as determined by a physical examination, from the PD weighted images (Suckling et al., 1999a).
electrocardiography, and routine laboratory investiga- Each voxel in the mask was then categorised in terms of
tions. Individuals with a history of severe head trauma, the proportion occupied by grey matter, white matter,
neurological disorders, and/or other medical disorders CSF or dura/blood vessels. This algorithm partitioned
that might have significantly affected brain function or the feature space formed by the two MR echoes (PD and
structure were excluded, as well as individuals who used T2-weighting), using a four-class modified fuzzy
alcohol in excess of five standard units per day or illicit clustering scheme, and assigned continuous member-
drugs on a weekly basis. ship of each tissue class to every voxel (Suckling et al.,
The study was approved by the local medical ethics 1999b). Axial non-uniformity of image contrast, due to
committee, and all the subjects gave written informed the reduction in sensitivity at the edges of the
consent in accordance with the committee's guidelines. transmitting/receiving coil, was corrected with a moving
window scheme. Classifying data in this manner allows
2.2. Clinical and diagnostic procedures for changes in the distribution of voxels in feature space.
For a detailed description, see Suckling et al. (1999b).
Patients were interviewed with the Life Chart (WHO, Total cerebral tissue volumes were obtained by
1992), BPRS (Lukoff et al., 1986; Overall and Gorham, summing over all proportions and multiplying by
1962), the PANNS (Kay et al., 1987, 1988) and were voxel volume.
additionally screened for symptoms listed in the OCCPI
(McGuffin et al., 1991). The computerised program 2.4. Metabolic stress paradigm (2-deoxy-glucose
OPCRIT (McGuffin et al., 1991) yielded the following protocol)
RDC-diagnoses: schizophrenia (n = 25) and schizo-
affective disorder (n = 6). To determine life-time history A full description of this paradigm applied to a larger
of alcohol and drug use, the Composite International sample can be found elsewhere (Marcelis et al., 2004).
Diagnostic Interview (CIDI) (Smeets and Dingemans, In brief, all subjects underwent double-blind adminis-
1993) was administered. All current medications were tration of the glucose analog 2DG and placebo, in
recorded. randomized order. The 2DG doses were 50 mg/kg
mixed in 100 ml of isotonic saline. Placebo was a
2.3. Image acquisition and processing comparable volume of isotonic saline (NaCl, 0.9%).
Both conditions (2DG/placebo) were given within one
2.3.1. Image acquisition week, with at least two days in between. Subjects had to
MRI scans were obtained at the Department of fast from midnight prior to both test days and were
Radiology, University Hospital Maastricht, The Nether- allowed to drink only water ad libitum. During the test,
lands, with a Gyroscan NT T-I1 (Philips Medical subjects rested supine in bed from 8:45 a.m. until 12:30
Systems) operating at 1.5 T. Three millimetre thick p.m. At 8:45 a.m., an intravenous catheter was inserted
interleaved two-dimensional dual-echo fast spin-echo in the antecubital fossa and kept patent with a slow drip
images (60 slices, 0.3 mm gap between slices) were of isotonic saline. At 9:50 a.m., two baseline venous
acquired and angled parallel to the clivus, covering the blood samples were taken 10 min and 0 min prior to
entire brain. Proton density (PD) weighted and T2- infusion. At 0 min, 2DG or placebo was infused over a
weighted images were acquired simultaneously (echo period of 20 min. Four more blood samples were taken
time (TE)1 = 20 ms, TE2 = 100 ms, TR = 4000 ms, echo at 60 min, 90 min, 120 min and 150 min after the
train length: 6, total acquisition time: 10 min 12 s). The infusion was started.
matrix size and field of view was set at 256 × 205 and Blood was collected in tubes containing 0.5 ml of
22 cm, respectively. The number of signal averages an EDTA (40 mg/ml) and Na2S2O5 (20 mg/ml)
was 1. solution. Plasma was obtained by centrifugation
(15 min at 3000 rpm) in a refrigerated centrifuge
2.3.2. Image processing (5 °C) and was then stored at − 80 °C until assaying. A
Image processing and computations were done on a 515 WATERS isocratic HPLC was used for assaying
SUN Ultra10 (Sun MicroSystems Inc., Mountain View, HVA, with a Symmetryshield RP18 25 cm column for
CA, USA) workstation with the BAMM software (Brain the separation of the compounds. Intra-assay variability
Activation and Morphological Mapping, University of was 5% for HVA. Inter-assay variability was 9% for
Cambridge, UK). Initially, a mask of parenchymal tissue HVA.
48 M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53
2.5. Statistical analyses
The data were analyzed with the STATA computer
program, version 8 (StataCorp., 2001). The variable
“condition” had two levels: the placebo condition
(reference) and the 2DG condition. HVA was sampled
on six occasions (time 1–6). Time points 1–6 were
divided into the variables timeA (time 1–2) and timeB
(time 3–6) reflecting the two pre- and the four post-
infusion measurement occasions. TimeB served as the
independent variable of interest, with timeA as covariate
to control for baseline values. The mean HVA level of Fig. 1. Effects of 2-deoxy-glucose and placebo on plasma HVA (ng/
ml) in 31 patients with psychosis. Data points represent mean plasma
the two pre-infusion samples for each person and each
HVA levels. Time 1 and 2 reflect the two pre-infusion (baseline)
condition was used to construct a baseline HVA variable occasions on which plasma HVA was measured (i.e., 10 min and 0 min
(HVA_base) (Marcelis et al., 2004). prior infusion). Times 3–6 reflect the four post-infusion sampling
To investigate the effect of global tissue volume on occasions: respectively, 60 min, 90 min, 120 min, and 150 min post-
HVA during metabolic stress, multilevel linear regres- infusion. The increase in HVA over time in the 2DG condition
compared to the placebo condition was statistically significant
sion analyses (see below) were conducted with HVA as
(condition × timeB interaction term, Likelihood Ratio Statistic (LRS)
the dependent variable and tissue volume, condition, = 84.93, p < 0.001).
timeB, as well as their interactions, as independent
variables. In addition, HVA-baseline, timeA, age, sex
and total brain volume were added as covariates to adjust (SD: 63.4); for CSF: 169.2 cm3 (SD: 32.0). Total cere-
for their a priori hypothesized confounding effects. bral brain volume (grey + white + CSF volume) was
As the average measure of HVA is assumed to vary 1274.1 cm3 (SD: 127.2). Mean levels of HVA (ng/ml) at
across persons, two observations will be more similar if the six measurement points during the stress and
they are from the same person. Our design of repeated placebo condition are presented in Fig. 1.
measures within the same person therefore compro- There was no evidence for an effect of antipsychotic
mised statistical independence of the observations. In medication dosage (expressed as standard haloperidol
order to deal with this issue, multilevel random equivalents) on brain tissue volume (β for grey matter:
regression models were fitted (Goldstein, 1987) with 1.01, 95% CI: − 3.19–5.21; β for white matter:− 3.52,
the XTREG module in STATA. The β is the fixed 95% CI:− 7.9–0.86; β for CSF: 2.5, 95% CI:− 1.08–
regression coefficient of the predictor in the multilevel 6.10).
model and can be interpreted identically to the estimate
in a unilevel regression analysis. Interaction terms were 3.2. Association between global tissue volumes and
evaluated by Likelihood Ratio test. HVA level changes during metabolic stress
3. Results There was a significant effect of condition on HVA
(β = 1.54, p < 0.001). In addition, a significant condi-
3.1. Subjects and descriptives tion × timeB interaction was found (Likelihood Ratio
Statistic (LRS) = 84.93, p < 0.001), indicating an in-
The sample consisted of 15 men and 16 women. The crease in HVA over time in the 2DG condition compared
mean age was 30.7 years (S.D.: 7.4) and mean age of to the placebo condition.
first psychotic symptoms was 22.1 years (S.D.: 5.8). In Fig. 2A, HVA level differences between the stress
The mean duration of illness was 8.6 years (S.D.: 5.7). and placebo condition at the six measurement points
Twenty-eight patients were receiving antipsychotic are depicted for three grey matter volume groups,
medication (atypical: n = 15; typical: n = 13). Mean suggestive of interaction. This hypothesis was exam-
current dosage in terms of standard haloperidol ined statistically by fitting a three-way interaction
equivalents was 4.99 (S.D.: 3.06). Of the 28 patients, between grey matter volume, condition, and time B,
12 patients also used a benzodiazepine, and 4 used an which yielded a significant negative grey matter × con-
antidepressant. dition × timeB interaction (β = − 0.0036, p < 0.021). This
Mean tissue volumes were, for grey matter: negative interaction indicates that the increase in HVA
559.5 cm3 (SD: 64.0); for white matter: 545.4 cm3 in the stress condition was stronger in patients with
M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53 49
HVA during stress was measured in the group with the
highest white matter volumes, plotting of HVA level
differences between 2DG and placebo conditions over
time separately for each tertile of white matter did not
reveal a dose–response relationship (Fig. 2B).
For the measure of CSF volume, no significant
CSF × condition × timeB interaction was apparent, al-
though the direction of the effect was similar (β =
− 0.0008, p < 0.80).
In order to examine whether the effect of grey matter
volume was independent of white matter volume and
vice versa, both interaction terms were entered in the
analyses, which reduced both the effect size and
statistical significance of the interaction with grey
matter volume, as well as of the interaction with white
matter volume (grey matter × condition × timeB: β =
− 0.0027, p < 0.19; white matter × condition × timeB:
β = −0.00149, p < 0.47). This suggests that the effects
of grey and white matter volume on HVA reactivity are
Total grey and white matter volume in patients with
psychotic disorder were negatively associated with HVA
reactivity during metabolic stress, suggesting that
reduced grey and white matter volume lead to an
enhanced DA/NA-mediated stress response. CSF was
not significantly associated with HVA reactivity,
Fig. 2. These figures reflect the differences in mean plasma HVA levels
(ng/ml) between the two conditions (i.e., 2DG and placebo condition),
suggesting that altered CSF volume does not affect the
stratified by brain volume group. The lines in the figure in (A) indicate DA/NA-mediated stress response.
three grey matter tertiles and the lines in the figure in (B) indicate three The metabolic stress paradigm has been used
white matter tertiles: lowest volume group (open squares), middle previously in preclinical and clinical studies. For
volume group (closed squares), and highest volume group (closed example, studies in rats and healthy volunteers have
triangle). Time 1 and time 2 reflect the two pre-infusion (baseline)
sampling occasions (i.e., 10 min and 0 min prior infusion). Times 3–6
shown a 2DG-induced increase in cerebral blood flow to
reflect the four post-infusion measurement points at, respectively, multiple cortical and subcortical regions (Breier et al.,
60 min, 90 min, 120 min, and 150 min post-infusion. 1993a; Elman et al., 1999), as well as a 2DG-induced
increase in striatal dopamine release using [11C] PET in
healthy subjects (Adler et al., 2000). The paradigm was
lower grey matter volume than in patients with higher first applied to patients with schizophrenia by Breier et
grey matter volume. Adjustment for age, sex, total al. (Breier, 1989; Breier et al., 1993b), and their findings
brain volume, and medication dosage did not affect the of altered HVA reactivity in this patient group have
results (β = − 0.0041, p < 0.005). recently been replicated in a larger sample (Marcelis et
For white matter volume, a significant negative white al., 2004).
matter × condition × timeB interaction was found (β = The association between grey matter volume and
− 0.0032, p < 0.046), indicating that the increase in HVA HVA reactivity to metabolic stress is consistent with a
during metabolic stress was stronger in patients with prior report on the relationship between decreased grey
lower white matter volume than in patients with higher matter volume in the prefrontal cortex and excessive
white matter volume. Adjustment for age, sex, total HVA release in patients with schizophrenia, measured
brain volume and medication dosage did not change during similar stress conditions (Breier et al., 1993b). In
effect size and associated significance level (β = a sample of three times as many patients, and for the first
− 0.0031, p < 0.039). Although the smallest increase in time since the publication of Breier more than 10 years
50 M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53
ago, these findings have now been independently dopamine release by loss of cortical control). This
replicated by the present study, in that reduced cerebral mechanism is thought to be more pronounced during
grey matter alterations were associated with increased perturbing than during resting conditions (Breier et al.,
plasma HVA levels during 2DG administration. Al- 1993b).
though subregions of grey matter such as the prefrontal However, as the present study yielded only indirect
cortex were not examined, the present investigation evidence by examining global tissue volumes in
extends the earlier findings (Breier et al., 1993b) by relation to the DA/NA mediated stress response, this
investigating not only grey matter in relation to the hypothesized dysfunctional neurocircuit involved in
stress measure, but also white matter and CSF. stress regulation needs to be more directly tested using
White matter provides the physiological basis for techniques such as positron emission tomography
cortico-cortical and subcortico-cortical connections (PET) and single photon emission tomography
and there is accumulating evidence for abnormal (SPECT). Dopamine receptor imaging studies have
connectivity in schizophrenia (Friston and Frith, 1995; already produced direct evidence for a cortical origin
Hubl et al., 2004). Recent investigations into the of the upregulated striatal dopamine function in
organization of cerebral white matter are indicative of schizophrenia (Kapur and Lecrubier, 2003). Whether
deficient intra- and interhemispheric connectivity in the hypothesized DA dysregulation is reflective of a
patients with schizophrenia (Burns et al., 2003; state, of a trait, or the combination of trait/state also
Hulshoff Pol et al., 2004; Kubicki et al., 2003; Zhou warrants further investigation. Recent evidence sug-
et al., 2003). The present results showed that gests that both components are involved: a state
decreased white matter volume was associated with component associated with psychotic exacerbations
an enhanced DA/NA mediated stress response, and a trait component present in remitted patients and
although the evidence was less strong than for grey in schizophrenia spectrum disorder (Abi-Dargham et
matter and might plausibly be attributed to the al., 2004).
correlation between grey and white matter. Despite CSF volume, in contrast to grey and white matter
the lack of clarity concerning the exact relationship volume, was not associated with altered HVA reactivity.
between grey and white matter, reductions in these This suggests that altered CSF volume is not part of the
tissue volumes were associated with excessive DA/NA same neurobiological substrate that leads to an enhanced
release following metabolic stress. central stress response.
Reduced grey matter may reflect widespread (in-
cluding prefrontal) cortical volume loss. White matter 4.1. Methodological considerations
reduction may indicate impairments in the connections
between the (prefrontal) cortex and subcortical struc- Much of the plasma HVA originates from central and
tures. The present findings may fit the model postulating peripheral noradrenaline (NA) systems. Even under
that stress-induced increases in mesocortical prefrontal fasting conditions, around 75% of plasma HVA derives
dopamine activity are involved in regulating subcortical from NA neuronal metabolism (Kopin et al., 1988).
dopamine activity, by exerting an inhibitory influence Nevertheless, plasma HVA changes also reflects central
on striatal dopamine. Indeed, reduced grey matter dopamine (DA) activity (Amin et al., 1992), or can at
volume in schizophrenia may impact on cortical least be regarded as a central response to stress (Marcelis
dopamine function and diminish its “brake” function et al., 2004).
on the striatal dopamine system, resulting in excessive Global tissue volumes, and not specific brain areas,
release of striatal dopamine following even mild stress were investigated in relation to stress reactivity. In a
(Laruelle, 2000). The aberrant stress regulation system meta-analysis, decreases in grey matter of around 2%
in schizophrenia may be the consequence of primary and in white matter of around 1% have been found in
deficits of the prefrontal cortex, but could be the result patients versus controls (Wright et al., 2000). Although
of abnormal inputs due to alterations in other regions these grey and white matter changes are not equally
such as mesotemporal structures, which are often found distributed but are more pronounced in certain areas
to be affected in schizophrenia (Breier et al., 1992a; than in others, they are not specific to any particular
Heinz et al., 2003). brain area, and findings regarding sub-areas of the brain
Thus, grey and white matter deficits may mediate the are not as consistent as the findings regarding global
altered HVA response to stress, assuming that these grey and white matter changes. Thus, changes in global
global tissue alterations reflect dysfunctional cortico- tissue volumes are among the most robust in the
subcortical circuitry (i.e., dysinhibition of striatal literature and are arguably most suitable in the search for
M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53 51
associations between brain measures and clinical 4.2. Conclusion
A possible shortcoming of the current study is the This investigation explored whether changes in brain
absence of a control group which precludes definite structure in schizophrenia may affect central nervous
conclusions as regards the relevance of the findings for system functioning through a dysregulated dopaminer-
schizophrenia. However, investigating the functional gic stress response. The robust measures of grey and
correlate of a structural brain abnormality is relevant white matter volume, but not CSF volume, were
and biologically plausible in a population that is known negatively associated with the central stress response.
to exhibit the abnormality in question (i.e., individuals The findings support the hypothesis that compromised
with schizophrenia). This was our rationale for neurocircuits, in terms of dysfunctional cortico-subcor-
examining the association between tissue volumes and tical connections, may provide the anatomical basis for
stress-induced plasma HVA in patients only, similar to stress-induced increases in striatal dopamine, which
the approach used in a previous report on the may consequently affect psychosis susceptibility. Neu-
association between prefrontal cortex volume and roreceptor imaging techniques, such as PET and SPECT,
2DG-induced HVA increase in patients with schizo- which can be used to more directly assess regional
phrenia (Breier et al., 1993b). Moreover, the present cerebral dopamine concentrations and fluctuations
findings have face validity, in that they replicate and therein provide the tools to further test this hypothetical
support findings and hypotheses previously described in pathway mediating the central stress response.
the literature (Breier et al., 1993b; Kapur and Lecrubier,
Almost all patients were taking an antipsychotic
medication that influences dopamine levels. However, This study was supported by the Dutch Brain Society
patients with schizophrenia have a much stronger HVA and the Dutch Prevention Fund.
increase than controls during 2-DG exposure, indicating We thank Truda Driesen for her assistance in data
that (chronic) antipsychotic treatment does not preclude collection.
stress-induced increases in dopamine function (Breier et
al., 1993b; Marcelis et al., 2004). Moreover, antipsy- References
chotic medicated and non-medicated patients do not
show differences in HVA reactivity during metabolic Abi-Dargham, A., Kegeles, L.S., Zea-Ponce, Y., Mawlawi, O.,
Martinez, D., Mitropoulo, V., O'Flynn, K., Koenigsberg, H.W.,
stress (Breier et al., 1993b). Acute and chronic Van Heertum, R., Cooper, T., Laruelle, M., Siever, L.J., 2004.
benzodiazepine treatment has been found to diminish Striatal amphetamine-induced dopamine release in patients with
the effect of stress-induced activation of the mesocor- schizotypal personality disorder studied with single photon
tical DA system (Hegarty and Vogel, 1995). If emission computed tomography and [123I]iodobenzamide. Biol.
benzodiazepine use could have introduced a bias in Psychiatry 55, 1001–1006.
Adler, C.M., Elman, I., Weisenfeld, N., Kestler, L., Pickar, D., Breier,
the present results, this would presumably have led to an A., 2000. Effects of acute metabolic stress on striatal dopamine
underestimation of the strength of the association release in healthy volunteers. Neuropsychopharmacology 22 (5),
between tissue volume and HVA reactivity, as the latter 545–550.
would have been stronger in the absence of benzodiaz- Amin, F., Davidson, M., Davis, K.L., 1992. Homovanillic acid
measurement in clinical research: a review of methodology.
Schizophr. Bull. 18 (1), 123–148.
It has recently been suggested that antipsychotic Breier, A., 1989. A.E. Bennett award paper. Experimental approaches
medication may affect brain morphology (Dazzan et to human stress research: assessment of neurobiological mechan-
al., 2005; Lieberman et al., 2005). In the present study, isms of stress in volunteers and psychiatric patients. Biol.
we were not able to correct for lifetime medication Psychiatry 26 (5), 438–462.
dose, but (1) adjustment for current antipsychotic Breier, A., Buchanan, R.W., Elkashef, A., Munson, R.C.,
Kirkpatrick, B., Gellad, F., 1992a. Brain morphology and
dosage did not affect the strength nor the significance schizophrenia. A magnetic resonance imaging study of limbic,
of the three-way interaction term in the main analyses, prefrontal cortex, and caudate structures. Arch. Gen. Psychi-
and (2) there was no evidence of any direct effect of atry 49, 921–926.
current dosage on the three types of brain tissue Breier, A., Davis, O., Buchanan, R., Listwak, S.J., Holmes, C., Pickar,
volume. These findings make it unlikely that the dose– D., Goldstein, D.S., 1992b. Effects of alprazolam on pituitary–
adrenal and catecholaminergic responses to metabolic stress in
response association between tissue volume and stress- humans. Biol. Psychiatry 32 (10), 880–890.
induced HVA increase can be fully explained by the Breier, A., Crane, A.M., Kennedy, C., Sokoloff, L., 1993a. The effects
effects of antipsychotic medication. of pharmacologic doses of 2-deoxy-D-glucose on local cerebral
52 M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53
blood flow in the awake, unrestrained rat. Brain Res. 618 (2), debrisoquin treatment: validation in monkeys treated with MPTP.
277–282. Neuropsychopharmacology 1 (2), 119–125.
Breier, A., Davis, O.R., Buchanan, R.W., Moricle, L.A., Munson, R. Kubicki, M., Westin, C., Nestor, P.G., Wible, C.G., Frumin, M., Maier,
C., 1993b. Effects of metabolic perturbation on plasma homo- S.E., Kikinis, R., Jolesz, F.A., McCarley, R.W., Shenton, M.E.,
vanillic acid in schizophrenia. Relationship to prefrontal cortex 2003. Cingulate fasciculus integrity disruption in schizophrenia: a
volume. Arch. Gen. Psychiatry 50 (7), 541–550. magnetic resonance diffusion tensor imaging study. Biol. Psychi-
Burns, J., Job, D., Bastin, M.E., Whalley, H., Macgillivray, T., atry 54, 1171–1180.
Johnstone, E.C., Lawrie, S.M., 2003. Structural disconnectivity in Laruelle, M., 2000. The role of endogenous sensitization in the
schizophrenia: a diffusion tensor magnetic resonance imaging pathophysiology of schizophrenia: Implications from recent brain
study. Br. J. Psychiatry 182, 439–443. imaging studies. Brain Res. Rev. 31, 371–384.
Davis, KL., Kahn, R.S., Ko, G., Davidson, M., 1991. Dopamine in Laruelle, M., Abi-Dargham, A., 1999. Dopamine as the wind of
schizophrenia: a review and reconceptualization. Am. J. Psychiatry the psychotic fire: new evidence from brain imaging studies.
148, 1474–1486. J. Psychopharmacol. 13, 358–371.
Dazzan, P., Morgan, K.D., Orr, K., Hutchinson, G., Chitnis, X., Lieberman, J.A., Tollefson, G.D., Charles, C., Zipursky, R., Sharma,
Suckling, J., Fearon, P., McGuire, P., Mallet, R.M., Jones, P.B., T., Kahn, R.S., Keefe, R.S.E., Green, A.I., Gur, R.E., McEvoy, J.,
Leff, J., Murray, R.M., 2005. Different effects of typical and Perkins, D., Hamer, R.M., Gu, H., Tohen, M., 2005. Antipsychotic
atypical antipsychotics on grey matter in first episode drug effects on brain morphology in first-episode psychosis. Arch.
psychosis: the AESOP study. Neuropsychopharmacology 30 Gen. Psychiatry 62, 361–370.
(4), 765–774. Lukoff, D., Nuechterlein, K.H., Ventura, J., 1986. Manual for the
Deutch, A.Y., Clark, W.A., Roth, R.H., 1990. Prefrontal cortical Expanded Brief Psychiatric Rating Scale. Schizophr. Bull. 12,
dopamine depletion enhances the responsiveness of the mesolim- 594–602.
bic dopamine neurons to stress. Brain Res. 521 (1–2), 311–315. Marcelis, M., Myin-Germeys, I., Suckling, J., Woodruff, P., Hofman,
Elman, I., Sokoloff, L., Adler, C.M., Weisenfeld, N., Breier, A., 1999. P., Bullmore, E., Delespaul, Ph., Van Os, J., 2003a. Cerebral tissue
The effects of pharmacological doses of 2-deoxyglucose on alterations and daily life experience in psychosis. Acta Psychiatr.
cerebral blood flow in healthy volunteers. Brain Res. 815 (2), Scand. 107, 54–59.
243–249. Marcelis, M., Suckling, J., Woodruff, P., Hofman, P., Bullmore, E.,
Friston, K.J., Frith, C.D., 1995. Schizophrenia: a disconnection Van Os, J., 2003b. Searching for a structural endophenotype in
syndrome? Clin. Neurosci. 3 (2), 89–97. psychosis using computational morphometry. Psychiatry Res.
Glenthoj, B.Y., 1995. The brain dopaminergic system. Pharmacolog- Neuroimaging 122, 153–167.
ical, behavioural and electrophysiological studies. Dan. Med. Bull. Marcelis, M., Cavalier, E., Gielen, J., Delespaul, Ph., Van Os, J., 2004.
42, 1–21. Abnormal response to metabolic stress in schizophrenia: marker of
Goldstein, H., 1987. Multilevel Models in Educational and Social vulnerability or acquired sensitization? Psychol. Med. 34 (6),
Research. Griffin, London. 1103–1111.
Hegarty, A.A., Vogel, W.H., 1995. The effect of acute and chronic McGuffin, P., Farmer, A., Harvey, I., 1991. A polydiagnostic
diazepam treatment on stress-induced changes in cortical dopa- application of operational criteria in studies of psychotic illness.
mine in the rat. Pharmacol. Biochem. Behav. 52 (4), 771–778. Development and reliability of the OPCRIT system [news]. Arch.
Heinz, A., Romero, B., Gallinat, J., Juckel, G., Weinberger, D.R., Gen. Psychiatry 48 (8), 764–770.
2003. Molecular brain imaging and the neurobiology and Mitropoulou, V., Goodman, M., Sevy, S., Elman, I., New, A.S.,
genetics of schizophrenia. Pharmacopsychiatry 36 (Suppl 3), Iskander, E.G., Silverman, J.M., Breier, A., Siever, L.J., 2004.
S152–S157. Effects of acute metabolic stress on the dopaminergic and pituitary-
Hubl, D., Koenig, T., Strik, W., Federspiel, A., Kreis, R., Boesch, C., adrenal axis activity in patients with schizotypal personality
Maier, S.E., Schroth, G., Lovblad, K., Dierks, T., 2004. Pathways disorder. Schizophr. Res. 70 (1), 27–31.
that make voices: white matter changes in auditory hallucinations. Overall, J.E., Gorham, D.R., 1962. The Brief Psychiatric Rating Scale.
Arch. Gen. Psychiatry 61 (7), 658–668. Psychol. Rep. 10, 779–812.
Hulshoff Pol, H.E., Schnack, H.G., Mandl, R.C.W., Cahn, W., Collins, Smeets, R., Dingemans, P., 1993. Composite International Diagnostic
D.L., Evans, A.C., Kahn, R.S., 2004. Focal white matter density Interview (CIDI). World Health Organization.
changes in schizophrenia: reduced inter-hemispheric connectivity. Spitzer, R.L., Endicott, J., Robbins, E., 1978. Research Diagnostic
Neuroimage 21, 27–35. Criteria (RDC) for a Selected Group of Functional Psychoses.
Kapur, S., 2003. Psychosis as a state of aberrant salience: a framework Biometrics Research Division, New York State Psychiatric
linking biology, phenomenology, and pharmacology in schizo- Institute, New York.
phrenia. Am. J. Psychiatry 160, 13–23. StataCorp, 2001. STATA Statistical Software: Release 8.0. College
Kapur, S., Lecrubier, Y., 2003. Dopamine in the Pathophysiology and Station, Texas.
Treatment of Schizophrenia—New Findings. Martin Dunitz- Suckling, J., Brammer, M.J., Lingford-Hughes, A., Bullmore, E.T.,
Taylor & Francis Group, London, United Kingdom. 1999a. Removal of extracerebral tissues in dual-echo magnetic
Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative resonance images via linear scale-space features. Magn. Reson.
syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13 Imaging 17, 247–256.
(2), 261–276. Suckling, J., Sigmundsson, T., Greenwood, K., Bullmore, E.T., 1999b.
Kay, S.R., Opler, L.A., Lindenmayer, J.P., 1988. Reliability and A modified fuzzy clustering algorithm for operator independent
validity of the positive and negative syndrome scale for brain tissue classification of dual echo MR images. Magn. Reson.
schizophrenics. Psychiatry Res. 23 (1), 99–110. Imaging 17, 1065–1076.
Kopin, I.J., Bankiewicz, K.S., Harvey-White, J., 1988. Assessment of Vermetten, E., Bremner, J.D., 2002. Circuits and systems in stress: I.
brain dopamine metabolism from plasma HVA and MHPG during Preclinical studies. Depress. Anxiety 15, 126–147.
M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53 53
Weinberger, D.R., Lipka, B.K., 1995. Cortical maldevelopment, anti- brain volumes in schizophrenia. Am. J. Psychiatry 157 (1),
psychotic drugs, and schizophrenia: a search for common ground. 16–25.
Schizophr. Res. 16, 87–110. Zhou, S., Suzuki, M., Hagino, H., Takahashi, T., Kawasaki, Y.,
WHO, 1992. WHO Coordinated Multicenter Study on the Course and Nohara, S., Seto, Y., Kurachi, H., 2003. Decreased volume
Outcome of Schizophrenia. World Health Organisation, Geneva. and increased asymmetry of the anterior limb of the internal
Wright, I.C., Rabe-Hesketh, S., Woodruff, P.W., David, A.S., capsule in patients with schizophrenia. Biol. Psychiatry 54,
Murray, R.M., Bullmore, E.T., 2000. Meta-analysis of regional 427–436.