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Impact of pscyhoimmunology in research at major psychoses
Biological challenge to schizophrenia
107. Biological challenge to schizophrenia
11 07·1 I Biological predictors of response to neuroleptlcs In schizophrenia
A.C. Altamura, A. Curreli. Institute of Psychiatry, University of Cagliarl, Cagliarl. Italy Some neurochemical, neuroendocrine and neuromorphological variables are Investigated in schizophrenia not only as pathophysiological detenninanls but also as possible prediclOlS of response to short-medium tenn neuroleptic treatment (NT). (I) Neurochemical data: Plasma homovanillic acid (pHVAl measurements showed that pre-treatment levels were higher In neuroleptic (NL) responsive patients than in refractory ones. Both the degree of pHVA Increase at onset of NT and the degree of pHVA decrease after several weeks 01 therapy have been correlated with the clinical response [1]. These data seem to suggest that drug responder schizophreniC patients undergo shilts in central dopaITIinerglc activity, to a greater extent than non responders. (II) Neuroendocrine data: The use of serum prolactin (PRLllevels has been proposed as an Index 01 response to NL Patients responder to NL have shown a relationship among serum NL., PRL levels and outcome (lower serum levels led to a higher relapse rale), whereas NL refractory tients have consistently failed to show such a relationship [2].Apart f~m ~thoPhYSiOlogical Implications, the dysregulation of the hypothalamic-pltu• ltary-adrenal axis In schizophrenic patients could have a predictive value, since persistent nonsuppresslon In schizophrenia seerns to be associated with a poor response to NT [3]. (III) Neuromorphologlcal data: Some structural brain abnonnalities, like ventricular enlargement, cortical and subcortical atrophy, could have Impli· cations In terms of NL response. Although this relationship Is uncertain, non responders would frequently show abnonnal neuromorphological patterns. (IV) Pharmacoklnetlc data: Differences in NL responsiveness among patients may partly reflect differences In drug bioavailability. During haloperi• dol therapy higher plasma concentrations of Its main metabolite, reduced hal ridol (R-HL). seem to be associated with a poorer antipsychotic ~se than in subjects path lower levels of R-HL and R-HUHL ratio [4]. In conclusion, present data do not unlvocally support the existence of a single predictor of response to NL and most of these .findlngs ~ve ~ poorty replicated possibly because 01 the heterogeneity of schizophreniC disorders. Moreover, a more rel~e .de~nition ~f the antipsychotic response, and of Its consistency and specifICity In relation to nuclear schizophrenic symptoms Is needed. Finally, the use of a combined multidimensional approach seems to be more promising than a single predictor strategy. References [11 DavIdsOn Metal. (1991): Eftectaol neurolepUC lreatmentonaymptomaot echlzoph,.. ill on plaSma homOV8I1U1ic ackt concentratlona. Atch. Gen. Psyc/lj8lty48: 91G-913. [2) ~araone SV el aI. (1987) ~m neuroiepUC levels. p~ levels and relapse: a two ear studY of schizophreniC outpatients. J. CUn. Psyc/lj8lty48: 151-154. [3) ~mura AC (1996): Hypothalamlc-pltultary-adranaJ axla In schizophrenia. BIoI. Pay• chisrry40: 559-561. [4) Al\8mura AC et aI. (1987): Haloperidol metabolism and antipsychotic elIect In IChlzophrenia. LBnCell: 814-815.
(!07-g] Neuromorpho[oglcal patterns of sch)zophrenla N.C. Andreasen, P. Nopoulos, M. Aaum, S. Amdt, G. Harris, T. Clzadlo. Mental Health Clinical Researc!l center. Dept of Psychia~ Iowa City, lowS. USA ObJective: To review the most recent data on neuroanalomlcal abnormalities In schizophrenia using measures of greylwhlte matter and CSF denSity and suleeVgyral anatomy. Methods: BRAINS software has been expanded to Include components that pennlt well-validated measures of three tissue subtypes (grey and white matter and CSF) and of surface complexity. These new measures are applied using combined PO, n, and T2 sequences within the same IndiVidual which Increases the amount and accuracy of the Information generated. These methods are applied to Informative aamples, such U first episode patlents, as weR as patients who have experienced schizophrenia on a chronic basis.
BIOL PSYCHIATRY 1997;42:15-297S
2938
Results: Patients suffering from schizophrenia differ from healthy volun• teers matched for gender and parental education on a variety of these new measures, Including surface complexity and tissue density. Conclusions: These results provide additional confirmation for anatom• iclstruetural abnormalities In schizophrenia that are already present at the lime 01 onset of Illness. The findings are consistent with a neurodevelopmental orlgin for schizophrenia The measures 01 sulcaVgyral pattenns can potentially be used to date the time that the developmental abnormality begins. References [1) Andreasen NC, Cohen G, Harris G, Clzadlo T, Parkklnen J. Rezal K, Swayze VW (1992): Image processing for the study of brain structure and function: Problerns and programs. J. N.uropsychlBlryCiin Neuroset.4: 125-133. (2) Andreasen NC, Harris G, Clzadlo T, Arndt S. O'leary OS, Swayze V, Flaum M (1994): TecI1nlquet lor measuring sulcaVgyraJ patterns in the brain as visualized lhonIgh MR acannlng: BRAINPLOT AND BRAINMAP. Proc. NaIL Acad. ScI. u.s.A 90: 93-97. (3) Cohen G, Andreasen NC, AJliger A, Arndt S, Kuan J, Yuh WTC, Ehrhardt J (1992): Segmentation techniques lor the classifICation of brain tissue using magnetic reso• nance Imaging. Psychiatry Research: N.urolmaglng 45: 33-61.
11 07-31 Impact of psycholmmunology In research at major psychoses M. Maes, A. Un, C. Altamura, H.Y. Meltzer, E. Bosmans, R. De Jong, G. Kenis. Clinical Researc!l center for Mental Health, AZ Stuivenberg. Antwerp, Belgium There Is now some evidence that an Immune response participates In the pathophysiology of schizophrenia and that antipsychotic drugs may modulate Immune functions (Maes et al. 1994, 1995, 1996). Activation of cells of the monocyte/macrophage lineage In schizophrenia Is suggested by: Increased plasma levels oIlnterleuki~ (IL~) and soluble IL~ receptor (sIL~R), Increased IL-1 in culture supematant and in plasma; and Increased plasma IL-1 receptor, antagonist (IL-1RA). Activation of T lymphocytes is suggested by Increased numbers of T lymphocytes, Increased plasma sIL-2R and Increased CSF IL-2. Schizophrenia is accompanied by lower plasma levels of CC16 (Clara cell protein), an endogenous anti-inflammatory agent which acts as an anti-cytokine. Typical antipsychotic drugs suppress the proliferation of lymphocytes In vitro, inhibit IL-2 production by activated lymphocytes In vitro, and diminish plasma levels of IL~ and IL~R In vfvo. Atypical antipsychotic drugs increase plasma sIL·2R. The purpose 01 this study was to examine I) whether schiZophrenia Is aecompe.nled by an Inflammatory or acute phase (AP) response; Ii) the relationships between lower plasma CC16 and Inflammatory markers; and III) the effects of antipsychotic agents on these variables. Methods: Forty normal volunteers and 102 schizophrenic subjectS had measurements of AP reactants, such as haptoglobin (Hp), fibrinogen (Fb), complement component 3 (C3C), C4, hemopaxin (Hpx); plasma CC16 before and after treatment with clozapine; or plasma CC16. IL~ and IL~R. Results: Schizophrenic patients had significantly higher plasma Hp. Fb, C3C, C4, and Hpx than normal controls. No significant differences In these AP reactants COUld be found between normal volunteers and medicated schizophrenic patients. In schizophrenia, there were significant inverse correlations between lower plasma CC16 and Increased IL~ and IL~R. Repeated administration of clozaplne significantly Increased plasma CC16. Conclusions: I) schizophrenia is accompanied by an AP response; ii) lowerplasma CC16 may underlie the Inflammatory response; iii) antipsychotic agents may normalize the AP response. There Is now evidence that periph• eral blood monocytes-T lymphocytes or lhelr products may act on central brain regions. Blood-bome or brain fonned eytokines, such as IL·1, IL·2 and IL~ modulate the tumover of brain monoamine systems, such as dopamine, serotonin and norepinephrine. Il-2 and lL~, for example, augment the re• lease of dopamine In selected brain regions, such as the hippocampus and the frontal cortex. Thus, the Immune and AP response In schIZophrenia may participate In the dopaminergic pathophysiology of schlzophronla References [1] Maes M, Meltzer HY, Bosmans E (1994) Immune-Inftammatory mar1
107. Biological challenge to schizophrenia
11 07·1 I Biological predictors of response to neuroleptlcs In schizophrenia
A.C. Altamura, A. Curreli. Institute of Psychiatry, University of Cagliarl, Cagliarl. Italy Some neurochemical, neuroendocrine and neuromorphological variables are Investigated in schizophrenia not only as pathophysiological detenninanls but also as possible prediclOlS of response to short-medium tenn neuroleptic treatment (NT). (I) Neurochemical data: Plasma homovanillic acid (pHVAl measurements showed that pre-treatment levels were higher In neuroleptic (NL) responsive patients than in refractory ones. Both the degree of pHVA Increase at onset of NT and the degree of pHVA decrease after several weeks 01 therapy have been correlated with the clinical response [1]. These data seem to suggest that drug responder schizophreniC patients undergo shilts in central dopaITIinerglc activity, to a greater extent than non responders. (II) Neuroendocrine data: The use of serum prolactin (PRLllevels has been proposed as an Index 01 response to NL Patients responder to NL have shown a relationship among serum NL., PRL levels and outcome (lower serum levels led to a higher relapse rale), whereas NL refractory tients have consistently failed to show such a relationship [2].Apart f~m ~thoPhYSiOlogical Implications, the dysregulation of the hypothalamic-pltu• ltary-adrenal axis In schizophrenic patients could have a predictive value, since persistent nonsuppresslon In schizophrenia seerns to be associated with a poor response to NT [3]. (III) Neuromorphologlcal data: Some structural brain abnonnalities, like ventricular enlargement, cortical and subcortical atrophy, could have Impli· cations In terms of NL response. Although this relationship Is uncertain, non responders would frequently show abnonnal neuromorphological patterns. (IV) Pharmacoklnetlc data: Differences in NL responsiveness among patients may partly reflect differences In drug bioavailability. During haloperi• dol therapy higher plasma concentrations of Its main metabolite, reduced hal ridol (R-HL). seem to be associated with a poorer antipsychotic ~se than in subjects path lower levels of R-HL and R-HUHL ratio [4]. In conclusion, present data do not unlvocally support the existence of a single predictor of response to NL and most of these .findlngs ~ve ~ poorty replicated possibly because 01 the heterogeneity of schizophreniC disorders. Moreover, a more rel~e .de~nition ~f the antipsychotic response, and of Its consistency and specifICity In relation to nuclear schizophrenic symptoms Is needed. Finally, the use of a combined multidimensional approach seems to be more promising than a single predictor strategy. References [11 DavIdsOn Metal. (1991): Eftectaol neurolepUC lreatmentonaymptomaot echlzoph,.. ill on plaSma homOV8I1U1ic ackt concentratlona. Atch. Gen. Psyc/lj8lty48: 91G-913. [2) ~araone SV el aI. (1987) ~m neuroiepUC levels. p~ levels and relapse: a two ear studY of schizophreniC outpatients. J. CUn. Psyc/lj8lty48: 151-154. [3) ~mura AC (1996): Hypothalamlc-pltultary-adranaJ axla In schizophrenia. BIoI. Pay• chisrry40: 559-561. [4) Al\8mura AC et aI. (1987): Haloperidol metabolism and antipsychotic elIect In IChlzophrenia. LBnCell: 814-815.
(!07-g] Neuromorpho[oglcal patterns of sch)zophrenla N.C. Andreasen, P. Nopoulos, M. Aaum, S. Amdt, G. Harris, T. Clzadlo. Mental Health Clinical Researc!l center. Dept of Psychia~ Iowa City, lowS. USA ObJective: To review the most recent data on neuroanalomlcal abnormalities In schizophrenia using measures of greylwhlte matter and CSF denSity and suleeVgyral anatomy. Methods: BRAINS software has been expanded to Include components that pennlt well-validated measures of three tissue subtypes (grey and white matter and CSF) and of surface complexity. These new measures are applied using combined PO, n, and T2 sequences within the same IndiVidual which Increases the amount and accuracy of the Information generated. These methods are applied to Informative aamples, such U first episode patlents, as weR as patients who have experienced schizophrenia on a chronic basis.
BIOL PSYCHIATRY 1997;42:15-297S
2938
Results: Patients suffering from schizophrenia differ from healthy volun• teers matched for gender and parental education on a variety of these new measures, Including surface complexity and tissue density. Conclusions: These results provide additional confirmation for anatom• iclstruetural abnormalities In schizophrenia that are already present at the lime 01 onset of Illness. The findings are consistent with a neurodevelopmental orlgin for schizophrenia The measures 01 sulcaVgyral pattenns can potentially be used to date the time that the developmental abnormality begins. References [1) Andreasen NC, Cohen G, Harris G, Clzadlo T, Parkklnen J. Rezal K, Swayze VW (1992): Image processing for the study of brain structure and function: Problerns and programs. J. N.uropsychlBlryCiin Neuroset.4: 125-133. (2) Andreasen NC, Harris G, Clzadlo T, Arndt S. O'leary OS, Swayze V, Flaum M (1994): TecI1nlquet lor measuring sulcaVgyraJ patterns in the brain as visualized lhonIgh MR acannlng: BRAINPLOT AND BRAINMAP. Proc. NaIL Acad. ScI. u.s.A 90: 93-97. (3) Cohen G, Andreasen NC, AJliger A, Arndt S, Kuan J, Yuh WTC, Ehrhardt J (1992): Segmentation techniques lor the classifICation of brain tissue using magnetic reso• nance Imaging. Psychiatry Research: N.urolmaglng 45: 33-61.
11 07-31 Impact of psycholmmunology In research at major psychoses M. Maes, A. Un, C. Altamura, H.Y. Meltzer, E. Bosmans, R. De Jong, G. Kenis. Clinical Researc!l center for Mental Health, AZ Stuivenberg. Antwerp, Belgium There Is now some evidence that an Immune response participates In the pathophysiology of schizophrenia and that antipsychotic drugs may modulate Immune functions (Maes et al. 1994, 1995, 1996). Activation of cells of the monocyte/macrophage lineage In schizophrenia Is suggested by: Increased plasma levels oIlnterleuki~ (IL~) and soluble IL~ receptor (sIL~R), Increased IL-1 in culture supematant and in plasma; and Increased plasma IL-1 receptor, antagonist (IL-1RA). Activation of T lymphocytes is suggested by Increased numbers of T lymphocytes, Increased plasma sIL-2R and Increased CSF IL-2. Schizophrenia is accompanied by lower plasma levels of CC16 (Clara cell protein), an endogenous anti-inflammatory agent which acts as an anti-cytokine. Typical antipsychotic drugs suppress the proliferation of lymphocytes In vitro, inhibit IL-2 production by activated lymphocytes In vitro, and diminish plasma levels of IL~ and IL~R In vfvo. Atypical antipsychotic drugs increase plasma sIL·2R. The purpose 01 this study was to examine I) whether schiZophrenia Is aecompe.nled by an Inflammatory or acute phase (AP) response; Ii) the relationships between lower plasma CC16 and Inflammatory markers; and III) the effects of antipsychotic agents on these variables. Methods: Forty normal volunteers and 102 schizophrenic subjectS had measurements of AP reactants, such as haptoglobin (Hp), fibrinogen (Fb), complement component 3 (C3C), C4, hemopaxin (Hpx); plasma CC16 before and after treatment with clozapine; or plasma CC16. IL~ and IL~R. Results: Schizophrenic patients had significantly higher plasma Hp. Fb, C3C, C4, and Hpx than normal controls. No significant differences In these AP reactants COUld be found between normal volunteers and medicated schizophrenic patients. In schizophrenia, there were significant inverse correlations between lower plasma CC16 and Increased IL~ and IL~R. Repeated administration of clozaplne significantly Increased plasma CC16. Conclusions: I) schizophrenia is accompanied by an AP response; ii) lowerplasma CC16 may underlie the Inflammatory response; iii) antipsychotic agents may normalize the AP response. There Is now evidence that periph• eral blood monocytes-T lymphocytes or lhelr products may act on central brain regions. Blood-bome or brain fonned eytokines, such as IL·1, IL·2 and IL~ modulate the tumover of brain monoamine systems, such as dopamine, serotonin and norepinephrine. Il-2 and lL~, for example, augment the re• lease of dopamine In selected brain regions, such as the hippocampus and the frontal cortex. Thus, the Immune and AP response In schIZophrenia may participate In the dopaminergic pathophysiology of schlzophronla References [1] Maes M, Meltzer HY, Bosmans E (1994) Immune-Inftammatory mar1