clozapine and Nervous-System-Diseases

Conventional antipsychotic drugs, used for a half century to treat a range of major psychiatric disorders, are being replaced in clinical practice by modern "atypical" antipsychotics, including aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone among others. As a class, the newer drugs have been promoted as being broadly clinically superior, but the evidence for this is problematic. In this brief critical overview, we consider the pharmacology, therapeutic effectiveness, tolerability, adverse effects and costs of individual modern agents versus older antipsychotic drugs. Because of typically minor differences between agents in clinical effectiveness and tolerability, and because of growing concerns about potential adverse long-term health consequences of some modern agents, it is reasonable to consider both older and newer drugs for clinical use, and it is important to inform patients of relative benefits, risks and costs of specific choices.

Topics: Antipsychotic Agents; Clozapine; Humans; Nervous System Diseases; Psychotic Disorders

Clozapine is increasingly being used for clinical indications in addition to treatment-resistant schizophrenia; this article reviews the relevant literature. The first section reassesses the risks associated with clozapine treatment, particularly agranulocytosis. The next section discusses its use for schizophrenia in patients who are treatment resistant, not treatment resistant, and intolerant of traditional drug treatments. Subsequent sections address its use in mood disorders, neurologic conditions, comorbid substance abuse, aggressive behavior, and childhood schizophrenia. Each includes the initial rationale for the use of clozapine in the disorder, a critical evaluation of the relevant literature, and theories as to why clozapine's unique pharmacodynamic profile may be efficacious for the specific condition. This body of literature suggests clozapine may be an effective treatment for a wide range of disorders.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Mood Disorders; Nervous System Diseases; Schizophrenia

The neurological effects of neuroleptic drugs are well known from the very beginning of their history and are even part of the initial definition of this therapeutic class. However, these effects are not necessary for an antipsychotic efficacy as demonstrated by the fully effective "atypical" neuroleptics, which induce minimal neurological side-effects. The neurobiological mechanisms underlying this "atypicity" are not well elucidated but could involve a preferential action on mesocorticolimbic dopaminergic system. This preferential action on mesocorticolimbic dopaminergic system. This specificity of action seem especially interesting in the case of patients suffering of severe tardive dyskinesia. Hence, the absence of rebond of preexistent dyskinesia when stopping a long term treatment with clozapine suggest that the pursuit of neuroleptic with this substance in dyskinetic patients would not worsen the long term prognosis of their dyskinesia. Available data on other atypical neuroleptics are insufficient to conclude if this benefit action on tardive dyskinesia is specific of clozapine or shared with other new neuroleptics.

Topics: Antipsychotic Agents; Brain; Clozapine; Dyskinesia, Drug-Induced; Humans; Nervous System Diseases; Neurologic Examination; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

This review will analyze the use of clozapine in patients with neurologic illness.. A review of the literature was performed. Attention is focused particularly on patients with seizure disorder, head injury, mental retardation, Parkinson's disease, Huntington's disease, tardive dyskinesia, and selected other neurological disorders.. This review discusses clinical difficulties/issues associated with clozapine therapy in patients with a variety of neurological disorders.. Although clozapine therapy should be reserved for those patients who are refractory to conventional psychotropic medications, when used appropriately it may offer a safe and effective way of improving quality of life for patients with behavioral symptoms and neurologic illness.

Topics: Antipsychotic Agents; Clozapine; Humans; Nervous System Diseases; Quality of Life; Treatment Outcome

The advent of clozapine has marked a major advance in the treatment of schizophrenia because of its low incidence of extrapyramidal side effects and superior efficacy. Because of a relatively high incidence of agranulocytosis, approved indications for use are limited to treatment-refractory or neuroleptic-intolerant patients with schizophrenia. However, an emerging body of literature suggests that clozapine may be preferable to typical neuroleptics for treating psychosis in certain neurologic disorders. In addition, clozapine may have a place in the treatment of movement disorders that are caused by or are a result of the pharmacologic treatment of some neurologic illnesses. In general, clozapine doses used in these settings are lower than that for treating psychosis in schizophrenia. This article reviews the experience with clozapine in selected neurologic disorders.

Topics: Clinical Trials as Topic; Clozapine; Drug Administration Schedule; Humans; Levodopa; Nervous System Diseases; Neurocognitive Disorders; Parkinson Disease; Tremor

Patients who develop psychosis or agitated behavior secondary to neurological disorders present a therapeutic dilemma. The authors review clinical efficacy and side effect profiles of clozapine in a cohort of 16 patients with various neurobehavioral disorders. One-third showed a marked decrease in symptoms while on clozapine. However, one-quarter developed an acute confusional state; of these, all had diffuse slowing on their baseline EEG prior to starting the drug.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Nervous System Diseases; Psychotic Disorders; Retrospective Studies

We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.

Topics: Adrenergic Uptake Inhibitors; Animals; Behavior, Animal; Biological Availability; Drug Discovery; Electroshock; Indicators and Reagents; Male; Mental Disorders; Nervous System Diseases; Quinoxalines; Quipazine; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Recombinant Proteins; Schizophrenia; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship

Neurologic soft signs (NSS) are considered a somatic feature associated with schizophrenia (DSM-IV) that are present in neuroleptic-treated, as well as untreated or first-episode patients. The aim of this study was to determine the incidence and severity of NSS in groups of schizophrenic patients treated with either a conventional neuroleptic medication, haloperidol (n = 37), or atypical antipsychotic medications, risperidone (n = 19), clozapine (n = 34), and olanzapine (n = 18). NSS were assessed with the Neurological Evaluation Scale (NES), whereas extrapyramidal symptoms (EPS), which occur more commonly with conventional neuroleptic treatment, were evaluated using the Simpson-Angus Scale. NES scores were not significantly different between groups. Slight differences were found for 2 items only. The haloperidol group showed higher scores for the "Romberg test," whereas the clozapine group showed higher scores for "short-term memory." There were significant correlations between EPS and NES total score in the haloperidol and risperidone groups. These results demonstrate an overall overlapping of NSS among the groups, confirming their substantial independence from neurologic implications of neuroleptic treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Haloperidol; Humans; Male; Nervous System Diseases; Neuropsychological Tests; Olanzapine; Risperidone; Schizophrenia; Severity of Illness Index

In this study, we examined the effect of post-treatment with clozapine on the neuropathological changes in the rat retrosplenial cortex induced by the administration of non-competitive NMDA receptor antagonist dizocilpine ((+)-MK-801). The maximal increase in vacuolized neurons, which are representative of neuropathology, was observed 4 hours after a single injection of dizocilpine (0.5 mg/kg s.c.), with a complete reversal of the neuropathology after 16-24 hours. The administration of clozapine (10 mg/kg, i.p.,) 4 hours after the administration of dizocilpine significantly decreased the number of vacuolized neurons in the retrosplenial cortex 6, 8 or 10 hours after administration of dizocilpine, compared to vehicle-treated animals. Furthermore, the administration of clozapine (5, 10 or 20 mg/kg i.p.) 4 hours after the administration of dizocilpine produced a significant decrease in the number of vacuolized neurons in the retrosplenial cortex in a dose-dependent manner when measure 6 hours post-dizocilpine. These results show that neuropathological changes in the rat retrosplenial cortex produced by dizocilpine can be attenuated by post-treatment with clozapine.

Topics: Animals; Antipsychotic Agents; Cerebral Cortex; Clozapine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Limbic System; Nervous System Diseases; Neurons; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Vacuoles

Topics: Adult; Clozapine; Female; Humans; Lithium; Male; Nervous System Diseases

Topics: Animals; Autonomic Nervous System; Clozapine; Dibenzazepines; Humans; Nervous System Diseases; Psychotic Disorders