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Remoxipride therapy in poorly responsive schizophrenics
316 performance of the prefrontal activation paradigm appeared disorganized and random on placebo, with L-dopa the activation pattern was relatively focused in the anterior frontal cortex and suppressed elsewhere. The effect was similar to that produced by apomorphine (Daniel, Berman, Weinberger, 1989) and amphetamine (Daniel, Weinberger, Kleinman et al.) in earlier studies and consistent with animal studies suggesting that catecholamines improve signal-to-noise ratio in the cortex.
Remoxipride therapy in poorly responsive schizophrenics R. Conley*, L. Dixon, J. An Nguyen, C. Tamminga,
R. Raymond
Maryland Psychiatric Research Center, University of Mayland, BaItimore, MD 21228, USA
Remoxipride is a substituted benzomide antipsychotic that has been demonstrated to have approximately equal efficacy to classical neuroleptics in double-blind clinical trials. It has a preclinical and clinical profile that makes it an interesting candidate for classification as an atypical antipsychotic. It is a D2 dopamine receptor selective antagonist that seems to have preferential action on the mesolimbic compared to the nigrostriatal dopaminergic system in both behavioral and receptor binding studies in animals. This binding profile is further supported by this drug’s relative lack of extrapyramidal side effects in man. This binding profile is similar to the probable dopaminergic binding profile of clozapine. Clozapine, however, has marked binding to serotonergic, anticholinergic, Dl dopaminergic and alpha-adrenergic activity, whereas remoxipride has sigma opiate receptor blockade as its only other significant effect. Study of remoxipride in poorly responsive schizophrenic patients is one way to test whether the differential efficacy of clozapine is secondary to mesolimbic preferential dopaminergic blockade. Thirteen DSM-III-R diagnosed patients (9 male, 4 female, mean age 39.3 years) were treated openly with remoxipride at 2.50-600 mg per day for four weeks. All patients met the criteria established by Kane et al. (1988) of treatment resistance: they had all failed to have a significant improvement in positive symptoms in at least three neuroleptic trials. Patients were further categorized as neuroleptic nonresponsive, defined as patients with a history of less than 5% clinical improvement on neuroleptics (N = 7) and poorly responsive defined as patients with a history of slight improvement on neuroleptics who still met Kane’s criteria (N = 6). Eleven patients completed the trial. Remoxipride treated patients showed some improvement in positive and negative symptoms of schizophrenia. Two patients met categorical criteria for clinical improvement as defined by Kane. The poorly responsive patients showed more improvement than the nonresponsive patients, who showed no real change on remoxipride. Remoxipride may be efficacious in treating poorly responsive schizophrenics. There also may be subcategories within the treatment resistant classification of patients with marked prognostic significance.
-3PPP effects on local cerebral glucose utilization in the rat L.B. Dixon*, F. Tarazi, J. Pongstaphone,
0. Shirakawa, J.R. Walters, D. Bergstom,
C.A. Tamminga
Maryland Psychiatric Research Center, University of Mayland, Baltimore, MD 21228, USA.
Partial dopamine (DA) agonists, including the prototypical 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3PPP), are currently of considerable pharmacologic interest in their action on schizophrenia, At low doses, -3PPP stimulates the autoreceptor, now thought to be of the D3 type, sufficiently to reduce DA release and neuronal firing. At higher doses, -3PPP blocks apomorphine’s postsynaptic actions at the D2 receptor. Thus, -3PPP may diminish DA-mediated transmission through two distinct actions. The goal of this study is to 1) its functional assess -3PPP action on local cerebral glucose utilization (LCGU) in rats to demonstrate localization at low and high doses; and 2) to compare -3PPP’s effects with that of a full dopamine agonist, apomorphine, and with a typical antagonist, haloperidol. Doses of -3PPP were determined from electrophysiological evidence of DA auto- and postsynaptic-receptor action. Low dose -3PPP produced significantly increased glucose uptake in several cortical areas (e.g., prefrontal, cingulate, sensorimotor, auditory, p < 0.05) as well as in limbic regions, including hippocampus, septal nucleus, nucleus accumbens and medial and basolateral amygdala (p ~0.05) compared with saline control. These areas overlap with the primary and secondary projection areas of the D3 dopamine system. The higher dose of -3PPP produced virtually no significant changes in LCGU. The distribution of metabolic changes induced by either the low (autoreceptor)
Remoxipride therapy in poorly responsive schizophrenics R. Conley*, L. Dixon, J. An Nguyen, C. Tamminga,
R. Raymond
Maryland Psychiatric Research Center, University of Mayland, BaItimore, MD 21228, USA
Remoxipride is a substituted benzomide antipsychotic that has been demonstrated to have approximately equal efficacy to classical neuroleptics in double-blind clinical trials. It has a preclinical and clinical profile that makes it an interesting candidate for classification as an atypical antipsychotic. It is a D2 dopamine receptor selective antagonist that seems to have preferential action on the mesolimbic compared to the nigrostriatal dopaminergic system in both behavioral and receptor binding studies in animals. This binding profile is further supported by this drug’s relative lack of extrapyramidal side effects in man. This binding profile is similar to the probable dopaminergic binding profile of clozapine. Clozapine, however, has marked binding to serotonergic, anticholinergic, Dl dopaminergic and alpha-adrenergic activity, whereas remoxipride has sigma opiate receptor blockade as its only other significant effect. Study of remoxipride in poorly responsive schizophrenic patients is one way to test whether the differential efficacy of clozapine is secondary to mesolimbic preferential dopaminergic blockade. Thirteen DSM-III-R diagnosed patients (9 male, 4 female, mean age 39.3 years) were treated openly with remoxipride at 2.50-600 mg per day for four weeks. All patients met the criteria established by Kane et al. (1988) of treatment resistance: they had all failed to have a significant improvement in positive symptoms in at least three neuroleptic trials. Patients were further categorized as neuroleptic nonresponsive, defined as patients with a history of less than 5% clinical improvement on neuroleptics (N = 7) and poorly responsive defined as patients with a history of slight improvement on neuroleptics who still met Kane’s criteria (N = 6). Eleven patients completed the trial. Remoxipride treated patients showed some improvement in positive and negative symptoms of schizophrenia. Two patients met categorical criteria for clinical improvement as defined by Kane. The poorly responsive patients showed more improvement than the nonresponsive patients, who showed no real change on remoxipride. Remoxipride may be efficacious in treating poorly responsive schizophrenics. There also may be subcategories within the treatment resistant classification of patients with marked prognostic significance.
-3PPP effects on local cerebral glucose utilization in the rat L.B. Dixon*, F. Tarazi, J. Pongstaphone,
0. Shirakawa, J.R. Walters, D. Bergstom,
C.A. Tamminga
Maryland Psychiatric Research Center, University of Mayland, Baltimore, MD 21228, USA.
Partial dopamine (DA) agonists, including the prototypical 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3PPP), are currently of considerable pharmacologic interest in their action on schizophrenia, At low doses, -3PPP stimulates the autoreceptor, now thought to be of the D3 type, sufficiently to reduce DA release and neuronal firing. At higher doses, -3PPP blocks apomorphine’s postsynaptic actions at the D2 receptor. Thus, -3PPP may diminish DA-mediated transmission through two distinct actions. The goal of this study is to 1) its functional assess -3PPP action on local cerebral glucose utilization (LCGU) in rats to demonstrate localization at low and high doses; and 2) to compare -3PPP’s effects with that of a full dopamine agonist, apomorphine, and with a typical antagonist, haloperidol. Doses of -3PPP were determined from electrophysiological evidence of DA auto- and postsynaptic-receptor action. Low dose -3PPP produced significantly increased glucose uptake in several cortical areas (e.g., prefrontal, cingulate, sensorimotor, auditory, p < 0.05) as well as in limbic regions, including hippocampus, septal nucleus, nucleus accumbens and medial and basolateral amygdala (p ~0.05) compared with saline control. These areas overlap with the primary and secondary projection areas of the D3 dopamine system. The higher dose of -3PPP produced virtually no significant changes in LCGU. The distribution of metabolic changes induced by either the low (autoreceptor)