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Schizophrenia Research 86 (2006) 45 – 53 www.elsevier.com/locate/schres 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 a 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 b Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK c Department of Radiology, University Hospital Maastricht, Maastricht, The Netherlands d Department of Psychiatry, Sheffield Cognition and Neuroimaging Laboratory, Academic Clinical Psychiatry, University of Sheffield, The Longley Centre, Norwood Grange Drive, Sheffield, S5 7JT, UK e Department of Psychiatry, University of Cambridge, UK f 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 Abstract 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: firstname.lastname@example.org (M. Marcelis). 0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.05.001 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 correlated. 4. Discussion 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 variables. 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, 2003). Acknowledgements 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). 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