Clozapine
Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective i...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Fitton, Andrew [verfasserIn] Heel, Rennie C. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
1990 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Drugs - Berlin [u.a.] : Springer, 1971, 40(1990), 5 vom: Nov., Seite 722-747 |
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| Übergeordnetes Werk: |
volume:40 ; year:1990 ; number:5 ; month:11 ; pages:722-747 |
| Links: |
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| DOI / URN: |
10.2165/00003495-199040050-00007 |
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| Katalog-ID: |
SPR033156174 |
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| 520 | |a Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... | ||
| 650 | 4 | |a Schizophrenia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Haloperidol |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Clozapine |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Chlorpromazine |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Tardive Dyskinesia |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Heel, Rennie C. |e verfasserin |4 aut | |
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10.2165/00003495-199040050-00007 doi (DE-627)SPR033156174 (SPR)00003495-199040050-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Clozapine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... Schizophrenia (dpeaa)DE-He213 Haloperidol (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 Chlorpromazine (dpeaa)DE-He213 Tardive Dyskinesia (dpeaa)DE-He213 Heel, Rennie C. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 5 vom: Nov., Seite 722-747 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:5 month:11 pages:722-747 https://dx.doi.org/10.2165/00003495-199040050-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 5 11 722-747 |
| spelling |
10.2165/00003495-199040050-00007 doi (DE-627)SPR033156174 (SPR)00003495-199040050-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Clozapine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... Schizophrenia (dpeaa)DE-He213 Haloperidol (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 Chlorpromazine (dpeaa)DE-He213 Tardive Dyskinesia (dpeaa)DE-He213 Heel, Rennie C. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 5 vom: Nov., Seite 722-747 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:5 month:11 pages:722-747 https://dx.doi.org/10.2165/00003495-199040050-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 5 11 722-747 |
| allfields_unstemmed |
10.2165/00003495-199040050-00007 doi (DE-627)SPR033156174 (SPR)00003495-199040050-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Clozapine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... Schizophrenia (dpeaa)DE-He213 Haloperidol (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 Chlorpromazine (dpeaa)DE-He213 Tardive Dyskinesia (dpeaa)DE-He213 Heel, Rennie C. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 5 vom: Nov., Seite 722-747 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:5 month:11 pages:722-747 https://dx.doi.org/10.2165/00003495-199040050-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 5 11 722-747 |
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10.2165/00003495-199040050-00007 doi (DE-627)SPR033156174 (SPR)00003495-199040050-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Clozapine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... Schizophrenia (dpeaa)DE-He213 Haloperidol (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 Chlorpromazine (dpeaa)DE-He213 Tardive Dyskinesia (dpeaa)DE-He213 Heel, Rennie C. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 5 vom: Nov., Seite 722-747 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:5 month:11 pages:722-747 https://dx.doi.org/10.2165/00003495-199040050-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 5 11 722-747 |
| allfieldsSound |
10.2165/00003495-199040050-00007 doi (DE-627)SPR033156174 (SPR)00003495-199040050-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Clozapine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... Schizophrenia (dpeaa)DE-He213 Haloperidol (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 Chlorpromazine (dpeaa)DE-He213 Tardive Dyskinesia (dpeaa)DE-He213 Heel, Rennie C. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 5 vom: Nov., Seite 722-747 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:5 month:11 pages:722-747 https://dx.doi.org/10.2165/00003495-199040050-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 5 11 722-747 |
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Enthalten in Drugs 40(1990), 5 vom: Nov., Seite 722-747 volume:40 year:1990 number:5 month:11 pages:722-747 |
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Enthalten in Drugs 40(1990), 5 vom: Nov., Seite 722-747 volume:40 year:1990 number:5 month:11 pages:722-747 |
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Schizophrenia Haloperidol Clozapine Chlorpromazine Tardive Dyskinesia |
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Fitton, Andrew @@aut@@ Heel, Rennie C. @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR033156174</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519202319.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s1990 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.2165/00003495-199040050-00007</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR033156174</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)00003495-199040050-00007-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">610</subfield><subfield code="q">ASE</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.40</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.38</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Fitton, Andrew</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Clozapine</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">1990</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. 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clozapine |
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Clozapine |
| abstract |
Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... |
| abstractGer |
Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... |
| abstract_unstemmed |
Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration Clozapine may be administered orally or intramuscularly. The manufacturer re... |
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Clozapine |
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Heel, Rennie C. |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR033156174</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519202319.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s1990 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.2165/00003495-199040050-00007</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR033156174</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)00003495-199040050-00007-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">610</subfield><subfield code="q">ASE</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.40</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.38</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Fitton, Andrew</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Clozapine</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">1990</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics. Pharmacodynamic Properties In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine $ D_{2} $-receptors, and produces a more potent blockade of central dopamine $ D_{1} $-, cholinergic, serotonergic $ S_{2} $-, histamine $ H_{1} $, and $ α_{1} $- and $ α_{2} $-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine $ D_{1} $- and $ D_{2} $-receptors; at clinically effective doses central dopamine $ D_{2} $-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine $ D_{1} $-receptor function and produces down-regulation of serotonergic $ S_{2} $-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans. Pharmacokinetic Properties Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement. Adverse Effects Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. 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