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Impaired niacin flushing in schizophrenia: Possible biochemical mechanisms
98 9. N e u r o c h e m i s t r y , Clinical
IMPAIRED NIACIN FLUSHING IN SCHIZOPHRENIA: POSSIBLE BIOCHEMICAL MECHANISMS C. N. Bennett,* D. F. Horrobin Laxdale Ltd, Stirling, Scotland, United Kingdom A reduced cutaneous flushing reaction in response to topical application of niacin has now been replicated in more than ten populations of schizophrenic patients. All investigators have found an impaired response in between 30% and 70% of patients: the abnormality is most clear in patients not on medication. The impaired response defines biologically a large sub-group of patients. Only a limited sequence of biochemical reactions can be involved. The final step in the reaction is vaso-dilatation by prostaglandin (PG)D2. The PGD2 is formed by PGD synthase and then by cyclo-oxygenase (COX)-1 and COX-2 enzymes from free arachidonic acid (AA). The AA is released from phosphatidylcholine (PC) by phospholipase (PL)A2 which is activated by niacin. The PC which forms the substrate for PLA2 is also newly formed in response to niacin. The PC is made from phosphatidyl- ethanolamine (PE) by the enzyme PE-methyltransferase (PEMT). PEMT depends for normal activity on the methylation cycle which utilizes folic acid and vitamin B 12. The AA-rich PE which forms the starting substrate for the reaction sequence must be present in adequate amounts if the flushing reaction is to take place. The whole biochemical sequence could be impaired by abnormalities in the structure or regulation of any one of the proteins involved. There is evidence that in schizophrenia the incorporation of AA into phospholipids, the methylation of phospholipids, and the activity of PLA2 are all abnormal. Such abnormalities may interact to produce the observed deficit in niacin flushing.
PLASMA HOMOVANILLIC ACID DIFFERENCES BETWEEN PREDOMINANT POSITIVE AND NEGATIVE FIRST-EPISODE SCHIZOPHRENIC PATIENTS M. Bernardo,* I. Baeza, R. Deulofeu, J. Goti, M. T. Plana
Institut Clfnic de Psiquiatria i Psicologia, Corporaci6 Sanit&ria Cl{nic - IDIBAPS, Barcelona, Spain The aim of the study was to look for a biological marker useful to contribute to the validation of the different symptomatic dimensions of schizophrenia within the dopaminergic hypothesis frame. A sample of 29 naive first-episode schizophrenic patients was divided in predominant positive (n= 19) or negative (n= 10) subtype depending on their PANSS subscales (positive minus negative) scores at first admission. Plasma homovanillic acid (pHVA) levels were determined both before and after 4 weeks of risperidone treatment. Patients with predominant negative symptoms had statistically significant higher pHVA levels both before (23.49_+13.30 ng/mt) and after (23.44 -+13.38 ng/ml) risperidone therapy than the positive ones (18.92 +11.04 and 13.43 _+13.43 ng/ml, respectively). Furthermore, pHVA concentration did not significantly change after the treatment
in negative patients, as opposite to the predominant positive ones. These findings suggest that patients with a predominant negative syndrome have higher central dopaminergic turnover measured by pHVA levels, that remains unmodified after antipsychotic treatment. Nevertheless, a bigger size of sample, improving methodological issues and other studies within this research area are needed to confirm the validity of pHVA as a tool to help to define the dimensions of schizophrenia. This study was supported by the 2000 Clinic Hospital Award and 1999 Fundacio Agusti Pedro i Ports Grant to Dr.I.Baeza. Predominant+ patients Predominant - patients pHVA before treatment
18.92 4- 11.04 ng/mI
23.494- 13.30 ng/ml
pHVA after 4 w. treat.
13.43 4- 13.43 ng/ml
23.44_+13.38 ng/ml
PLASMA LEVELS OF INTERLEUKIN-12 IN DRUG-NAIVE SCHIZOPHRENIC PATIENTS: CHANGES ASSOCIATED WITH CLINICAL RESPONSE TO NEUROLEPTIC TREATMENT B. Crespo-Facorro,* E. Carrasco-Marin, R. Perez-Iglesias, G. Pardo, E Sanchez-Velasco, E Leyva-Cobian, J. L. Vazquez-Barquero Psychiatry, University of Cantabria. College of Medicine. HU Marques de Valdecilla, Santander, Spain To investigate: (i) IL-12 plasma levels (total and p70 subunit) in drug-naive schizophrenic patients; and (ii) their relation with neuroleptic treatment and clinical improvement. Subjects were 26 individuals (14 M, 12 F) with schizophrenia spectrum disorders (including DSM IV criteria of schizophrenia, schizoaffective disorder or schizophreniform disorder) in the early stages of the illness. Patients were excluded if there was a previous history of substance abuse, mental retardation or organic brain disease. Only physically healthy patients, who had been not chronically treated with steroids or immunosuppressive drugs were included. Variables to detect clinical response included changes in BPRS, SANS, and SAPS scores at 6 weeks. Responder is defined when a reduction in total BPRS score >30% is demonstrated after 6 weeks of treatment. All subjects gave written informed consent. IL-12 serum levels (total and p70 subunit) were determined at three points: baseline, 1 week and 6-8 weeks after starting conventional neuroleptic treatment (olanzapine, haloperidol, or risperidone). Cytokine concentration were determined by ELISA with specific monoclonal antibodies. Polymorphism in the ILl2 promotor was also determined by RFLP. 21 out of 26 patients (81%) show a significant increase in IL-12 p70 and total levels after six weeks of treatment, compared to baseline measures. Among these 21 patients with a marked increase in IL-12, 20 individuals (95%) were responders to neuroleptic treatment. Correlational analysis demonstrated a significant (p<0.001) association between clinical improvement and increased 1L-12 levels. No differences in IL-12 promoter polymorphism in patients compared to healthy population were found. Our results suggest a strong association between clinical improvement after antipsychotic treatment and an increase in IL-12, total and p70, induction. Further studies will address the role of IL-12 in TH1-TH2 imbalance related to schizophrenia. Research grant:Fundacion Marques de Valdecilla 02/07
International Congress on Schizophrenia Research 2003
IMPAIRED NIACIN FLUSHING IN SCHIZOPHRENIA: POSSIBLE BIOCHEMICAL MECHANISMS C. N. Bennett,* D. F. Horrobin Laxdale Ltd, Stirling, Scotland, United Kingdom A reduced cutaneous flushing reaction in response to topical application of niacin has now been replicated in more than ten populations of schizophrenic patients. All investigators have found an impaired response in between 30% and 70% of patients: the abnormality is most clear in patients not on medication. The impaired response defines biologically a large sub-group of patients. Only a limited sequence of biochemical reactions can be involved. The final step in the reaction is vaso-dilatation by prostaglandin (PG)D2. The PGD2 is formed by PGD synthase and then by cyclo-oxygenase (COX)-1 and COX-2 enzymes from free arachidonic acid (AA). The AA is released from phosphatidylcholine (PC) by phospholipase (PL)A2 which is activated by niacin. The PC which forms the substrate for PLA2 is also newly formed in response to niacin. The PC is made from phosphatidyl- ethanolamine (PE) by the enzyme PE-methyltransferase (PEMT). PEMT depends for normal activity on the methylation cycle which utilizes folic acid and vitamin B 12. The AA-rich PE which forms the starting substrate for the reaction sequence must be present in adequate amounts if the flushing reaction is to take place. The whole biochemical sequence could be impaired by abnormalities in the structure or regulation of any one of the proteins involved. There is evidence that in schizophrenia the incorporation of AA into phospholipids, the methylation of phospholipids, and the activity of PLA2 are all abnormal. Such abnormalities may interact to produce the observed deficit in niacin flushing.
PLASMA HOMOVANILLIC ACID DIFFERENCES BETWEEN PREDOMINANT POSITIVE AND NEGATIVE FIRST-EPISODE SCHIZOPHRENIC PATIENTS M. Bernardo,* I. Baeza, R. Deulofeu, J. Goti, M. T. Plana
Institut Clfnic de Psiquiatria i Psicologia, Corporaci6 Sanit&ria Cl{nic - IDIBAPS, Barcelona, Spain The aim of the study was to look for a biological marker useful to contribute to the validation of the different symptomatic dimensions of schizophrenia within the dopaminergic hypothesis frame. A sample of 29 naive first-episode schizophrenic patients was divided in predominant positive (n= 19) or negative (n= 10) subtype depending on their PANSS subscales (positive minus negative) scores at first admission. Plasma homovanillic acid (pHVA) levels were determined both before and after 4 weeks of risperidone treatment. Patients with predominant negative symptoms had statistically significant higher pHVA levels both before (23.49_+13.30 ng/mt) and after (23.44 -+13.38 ng/ml) risperidone therapy than the positive ones (18.92 +11.04 and 13.43 _+13.43 ng/ml, respectively). Furthermore, pHVA concentration did not significantly change after the treatment
in negative patients, as opposite to the predominant positive ones. These findings suggest that patients with a predominant negative syndrome have higher central dopaminergic turnover measured by pHVA levels, that remains unmodified after antipsychotic treatment. Nevertheless, a bigger size of sample, improving methodological issues and other studies within this research area are needed to confirm the validity of pHVA as a tool to help to define the dimensions of schizophrenia. This study was supported by the 2000 Clinic Hospital Award and 1999 Fundacio Agusti Pedro i Ports Grant to Dr.I.Baeza. Predominant+ patients Predominant - patients pHVA before treatment
18.92 4- 11.04 ng/mI
23.494- 13.30 ng/ml
pHVA after 4 w. treat.
13.43 4- 13.43 ng/ml
23.44_+13.38 ng/ml
PLASMA LEVELS OF INTERLEUKIN-12 IN DRUG-NAIVE SCHIZOPHRENIC PATIENTS: CHANGES ASSOCIATED WITH CLINICAL RESPONSE TO NEUROLEPTIC TREATMENT B. Crespo-Facorro,* E. Carrasco-Marin, R. Perez-Iglesias, G. Pardo, E Sanchez-Velasco, E Leyva-Cobian, J. L. Vazquez-Barquero Psychiatry, University of Cantabria. College of Medicine. HU Marques de Valdecilla, Santander, Spain To investigate: (i) IL-12 plasma levels (total and p70 subunit) in drug-naive schizophrenic patients; and (ii) their relation with neuroleptic treatment and clinical improvement. Subjects were 26 individuals (14 M, 12 F) with schizophrenia spectrum disorders (including DSM IV criteria of schizophrenia, schizoaffective disorder or schizophreniform disorder) in the early stages of the illness. Patients were excluded if there was a previous history of substance abuse, mental retardation or organic brain disease. Only physically healthy patients, who had been not chronically treated with steroids or immunosuppressive drugs were included. Variables to detect clinical response included changes in BPRS, SANS, and SAPS scores at 6 weeks. Responder is defined when a reduction in total BPRS score >30% is demonstrated after 6 weeks of treatment. All subjects gave written informed consent. IL-12 serum levels (total and p70 subunit) were determined at three points: baseline, 1 week and 6-8 weeks after starting conventional neuroleptic treatment (olanzapine, haloperidol, or risperidone). Cytokine concentration were determined by ELISA with specific monoclonal antibodies. Polymorphism in the ILl2 promotor was also determined by RFLP. 21 out of 26 patients (81%) show a significant increase in IL-12 p70 and total levels after six weeks of treatment, compared to baseline measures. Among these 21 patients with a marked increase in IL-12, 20 individuals (95%) were responders to neuroleptic treatment. Correlational analysis demonstrated a significant (p<0.001) association between clinical improvement and increased 1L-12 levels. No differences in IL-12 promoter polymorphism in patients compared to healthy population were found. Our results suggest a strong association between clinical improvement after antipsychotic treatment and an increase in IL-12, total and p70, induction. Further studies will address the role of IL-12 in TH1-TH2 imbalance related to schizophrenia. Research grant:Fundacion Marques de Valdecilla 02/07
International Congress on Schizophrenia Research 2003