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The Effects of clozapine on plasma norepinephrine kinetics in schizophrenic patients
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1 mg /kg clozapine, demonstrated that the early gene cfos mRNA was localized in the ventral tegmental area of the midbrain, site of origin of the mesolimbic-mesocortical dopamine pathway, and in the anterior thalamus. With the hypothesis that the excitation of these midline nuclei may be important for the therapeutic effects of clozapine on 'negative' symptoms of schizophrenia, and that myoclonus and seizures reflect spread of excitation to motor systems which are not essential to the therapeutic effect, a double blind placebo controlled study of biweekly low dose (SO mg) clozapine has been initiated in treatment refractory patients with schizophrenia.
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THE EFFECTS OF CLOZAPINE ON PLASMA NOREPINEPHRINE KINETICS IN SCHIZOPHRENIC PATIENTS Igor Elman,David S. Goldstein, Courtney Holmes. CalebAdler, David Pickar, Alan Breier Experimental Therapeutics Branch. NIMH. Bethesda. MD 20892. USA Clozapine is an atypical neuroleptic with efficacy superior to that of conventional antipsychotic medications. Illuminating the mechanisms of clozapine 's therapeutic action has important implications for understanding the pathophysiology of psychosis. One of the unique features of clozapine, elevation in norepinephrine (NE) plasma levels, has been positively correlated with improvement in schizophrenic symptomatology. We applied a tracer kinetic approach to examine the effects of clozapine on the rate of NE entry (spillover) into the arterial plasma . Eleven c1ozapine, 9 fluphenazine and 6 placebo-treated schizophrenic patients received a continuous intravenous infusion of 3[H]-Iabeled NE. Blood samples were assayed for levels of NE, 3[H]-NE, the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), and 3[HJ-DHPG. Clozapine-treated patients had markedly elevated (p <0.001) spillover and similar plasma clearance of NE, compared to fluphenazine and placebo-treated patients. Clozapine did not prevent conversion of 3[H]-NE to 3[Hl-DHPG, indicating that clozapine does not block membrane transporter for NE. DHPG levels in clozapinetreated patients tended to be decreased, thus elevated NE levels are not likely to be accounted by cx2-adrenoceptor antagonism. These data suggest that clozapine produces increases in plasma NE levels in schizophrenic patients via diffuse stimulation of sympathoneural outflow.
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RISPERIDONE'S EFFECTS ON VERBAL WORKING MEMORY Michael F. Green, B.D. Marshall, William C. Wirshing, Donna Ames, Stephen R. Marder, SusanMcGurk, Robert S. Kern, Jim Mintz UCLA Research Center, Box 6022, Camarillo, CA 93011, USA Although treatment efficacy in schizophrenia is defined in terms of symptom reduction, newer antipsychotic medications
could potentially impact neurocognitive deficits. The current study evaluated the effects of risperidone on ve~bal working memory. Verbal working memory is of theoretical interest because it is linked to prefrontal activity; it is of practical interest because it is linked to psychosocial rehabilitation. Forty five treatment-resistant schizophrenic patients participated in a randomized, double-blind comparison of rispe ridone and haloperidol. Verbal working memory was assessed at baseline, after four weeks of fixed dose medication, and after four weeks of flexible dose medication. Risperidone treatment had a beneficial effect on verbal working memory compared with haloperidol treatment at both study phases (fixed and flexible dose) . The differential effect of risperidone was most prominent when baseline verbal working memory performan~ was low. Neither benztropine administration nor psychouc symptom severity were significantly related to performance at either phase. . The beneficial effects of risperidone on verbal working memory appear to be due, at least partially, to a direct effect of the drug, possibly through antagonism of the S·HT2A receptor. Results from this study suggest that phannaco.therapeutic efficacy for schizophrenia treatment could be considered in broad terms to include neurocognitive abilities.
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CLOZAPINE: ELEVATION OF MEMBRANE UNSATURATED LIPID LEVELS AS A NEW MECHANISM OF ACTION D.F. Horrobin ", A.I.M. Glen·, R.C. Cantrill Scotia Research Institute. Stirling, ScotlandFK94T and -High/and PsychiatricResearch Group. Inverness. Scotland IV36JU The mechanism of action of clozapine remains uncertain. New antipsychotic drugs developed on the basis.of the recep~or blocking profile of clozapine behave more like halopendol without side effects than like clozapine itself. We have explored other possible mechan isms. Some schizophrenics. especi~y those with the deficit syndrome, have low levels of the hi~ unsaturated lipids, arachidonic acid (AA) and docosahexa~onlc acid (DHA) in red cell membranes. Such low levels are likely to modify the function of receptors associated with membranes. We therefore measured red cell AA and DHA in eight schizophrenic individuals before starting c10zapine and after 8-16 weeks on the drug. In every individual AA and DHA le~els rose substantially (p
1 mg /kg clozapine, demonstrated that the early gene cfos mRNA was localized in the ventral tegmental area of the midbrain, site of origin of the mesolimbic-mesocortical dopamine pathway, and in the anterior thalamus. With the hypothesis that the excitation of these midline nuclei may be important for the therapeutic effects of clozapine on 'negative' symptoms of schizophrenia, and that myoclonus and seizures reflect spread of excitation to motor systems which are not essential to the therapeutic effect, a double blind placebo controlled study of biweekly low dose (SO mg) clozapine has been initiated in treatment refractory patients with schizophrenia.
"b~
THE EFFECTS OF CLOZAPINE ON PLASMA NOREPINEPHRINE KINETICS IN SCHIZOPHRENIC PATIENTS Igor Elman,David S. Goldstein, Courtney Holmes. CalebAdler, David Pickar, Alan Breier Experimental Therapeutics Branch. NIMH. Bethesda. MD 20892. USA Clozapine is an atypical neuroleptic with efficacy superior to that of conventional antipsychotic medications. Illuminating the mechanisms of clozapine 's therapeutic action has important implications for understanding the pathophysiology of psychosis. One of the unique features of clozapine, elevation in norepinephrine (NE) plasma levels, has been positively correlated with improvement in schizophrenic symptomatology. We applied a tracer kinetic approach to examine the effects of clozapine on the rate of NE entry (spillover) into the arterial plasma . Eleven c1ozapine, 9 fluphenazine and 6 placebo-treated schizophrenic patients received a continuous intravenous infusion of 3[H]-Iabeled NE. Blood samples were assayed for levels of NE, 3[H]-NE, the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), and 3[HJ-DHPG. Clozapine-treated patients had markedly elevated (p <0.001) spillover and similar plasma clearance of NE, compared to fluphenazine and placebo-treated patients. Clozapine did not prevent conversion of 3[H]-NE to 3[Hl-DHPG, indicating that clozapine does not block membrane transporter for NE. DHPG levels in clozapinetreated patients tended to be decreased, thus elevated NE levels are not likely to be accounted by cx2-adrenoceptor antagonism. These data suggest that clozapine produces increases in plasma NE levels in schizophrenic patients via diffuse stimulation of sympathoneural outflow.
(,6S
RISPERIDONE'S EFFECTS ON VERBAL WORKING MEMORY Michael F. Green, B.D. Marshall, William C. Wirshing, Donna Ames, Stephen R. Marder, SusanMcGurk, Robert S. Kern, Jim Mintz UCLA Research Center, Box 6022, Camarillo, CA 93011, USA Although treatment efficacy in schizophrenia is defined in terms of symptom reduction, newer antipsychotic medications
could potentially impact neurocognitive deficits. The current study evaluated the effects of risperidone on ve~bal working memory. Verbal working memory is of theoretical interest because it is linked to prefrontal activity; it is of practical interest because it is linked to psychosocial rehabilitation. Forty five treatment-resistant schizophrenic patients participated in a randomized, double-blind comparison of rispe ridone and haloperidol. Verbal working memory was assessed at baseline, after four weeks of fixed dose medication, and after four weeks of flexible dose medication. Risperidone treatment had a beneficial effect on verbal working memory compared with haloperidol treatment at both study phases (fixed and flexible dose) . The differential effect of risperidone was most prominent when baseline verbal working memory performan~ was low. Neither benztropine administration nor psychouc symptom severity were significantly related to performance at either phase. . The beneficial effects of risperidone on verbal working memory appear to be due, at least partially, to a direct effect of the drug, possibly through antagonism of the S·HT2A receptor. Results from this study suggest that phannaco.therapeutic efficacy for schizophrenia treatment could be considered in broad terms to include neurocognitive abilities.
bo~
CLOZAPINE: ELEVATION OF MEMBRANE UNSATURATED LIPID LEVELS AS A NEW MECHANISM OF ACTION D.F. Horrobin ", A.I.M. Glen·, R.C. Cantrill Scotia Research Institute. Stirling, ScotlandFK94T and -High/and PsychiatricResearch Group. Inverness. Scotland IV36JU The mechanism of action of clozapine remains uncertain. New antipsychotic drugs developed on the basis.of the recep~or blocking profile of clozapine behave more like halopendol without side effects than like clozapine itself. We have explored other possible mechan isms. Some schizophrenics. especi~y those with the deficit syndrome, have low levels of the hi~ unsaturated lipids, arachidonic acid (AA) and docosahexa~onlc acid (DHA) in red cell membranes. Such low levels are likely to modify the function of receptors associated with membranes. We therefore measured red cell AA and DHA in eight schizophrenic individuals before starting c10zapine and after 8-16 weeks on the drug. In every individual AA and DHA le~els rose substantially (p