Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clozapine has proven to be more effective than typical antipsychotics in treatment-refractory schizophrenic patients, and some evidence suggests that it may be particularly useful in treating the negative symptoms of schizophrenia. However, it is unclear whether this observation reflects improvement in "primary" or "secondary" negative symptoms. We hypothesized that a portion of clozapine's effect on negative symptoms would be related to an improvement in positive (psychotic and disorganization) symptoms, a decrease in extrapyramidal side effects (EPSE), and/or a decrease in depressive symptoms. The remainder of its effect would be related to a direct effect on the neural circuits or pathologic processes responsible for the negative symptoms. Twenty-nine treatment-refractory schizophrenics treated with clozapine for 6 weeks were studied. The core negative symptoms measured by the Scale for the Assessment of Negative Symptoms ([SANS] affective flattening, anhedonia/asociality, avolition/apathy, and alogia) all improved with clozapine treatment. Overall, there was a 31% improvement in negative symptoms, a 32% improvement in psychotic symptoms, and a 35% improvement in disorganization. The improvement in negative symptoms was correlated with improvement in disorganization, but not with improvement in psychotic symptoms, depression, or drug-induced EPSE. Although there was a correlation between improvement in negative symptoms and improvement in disorganization, there was a suggestion that the two are changing in parallel, but are independent of each other. It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia associated with negative symptoms.
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PMID:Clozapine's effect on negative symptoms in treatment-refractory schizophrenics. 814 34

Effects of two typical neuroleptics haloperidol and loxapine, and an atypical antipsychotic clozapine on excitatory synaptic transmission were examined in the CA1 area of rat hippocampal slices. Haloperidol (10 mumol) and loxapine (10 mumol) increased extracelllar evoked field potentials by an average of 57 and 125% of the control level respectively. Clozapine (50 mumol) induced a transient depression (21% of control) of the response followed by a small augmentation (10%). Examination of haloperidol actions using the whole cell clamp technique showed an increase in the amplitude of the excitatory postsynaptic current (e.p.s.c.) in response to the drug without any apparent changes in the resting membrane current. These data suggest that haloperidol and loxapine may act by enhancing excitatory synaptic transmission in some areas of the brain, and that novel antipsychotic clozapine differs in its mechanism of action.
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PMID:Haloperidol and loxapine but not clozapine increase synaptic responses in the hippocampus. 850 10

Schizophrenic patients in long-term neuroleptic monotherapy with clozapine (n = 100) and perphenazine, flupenthixol or zuclopentixol (controls, n = 100) were evaluated for extrapyramidal side effects (EPS) (blind) as well as other side effects and mental condition (non-blind). In both groups the patients had received neuroleptic treatment for a total of 14 years (median) and the present antipsychotic (clozapine or control drug) for 5 years. Thus the clozapine-treated patients had previously received traditional neuroleptics for 9 years (median). The study was both retrospective (0.3-19 years for clozapine, 0.3-24 years for control drug, by means of chart information) and prospective (1 year, with video-controlled evaluation of EPS). There was a significantly lower prevalence of tardive dyskinesia (TD) in clozapine treated patients than control patients, although prior to this treatment there were more TD patients in the clozapine group (P < 0.05). This lower level of TD in the clozapine group was related to a lower induction of new cases (P < 0.001) and a tendency towards greater disappearance of TD in the clozapine than in the control group (P = 0.07). Clozapine treated patients without TD had started clozapine and ceased traditional neuroleptics at an earlier age than those with TD. Parkinsonian signs were seen in 33% of the clozapine patients versus 61% of the control patients, mainly as hypokinesia; tremor in 3% versus 11% and rigidity in 0 versus 19%. Psychic akathisia was found in 14% versus 40% and motor akathisia in 7% versus 29% of the patients, all differences significantly in favor of clozapine. Clozapine treated patients also had less neuroleptic-induced emotional indifference and depression, but more autonomic side effects than controls.
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PMID:Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects. 893 15

Clozapine, an atypical antipsychotic, is mainly approved for the treatment of resistant schizophrenia. However, a substantial body of evidence suggests that it might be useful in other psychiatric indications, such as treatment-resistant depression, Parkinson's disease, and dementia. In this report we present the cases of three patients hospitalized at the psychiatric division of the Sheba Medical Center, diagnosed with major depressive disorder with cognitive impairment, whose presenting symptom was agitation. These patients were nonresponders to various treatment modalities. However, treatment with clozapine brought about a favorable response.
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PMID:Clozapine for the treatment of agitated-depressed patients with cognitive impairment: a report of three cases. 957 2

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.
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PMID:A fatal drug interaction between clozapine and fluoxetine. 972 31

1. The aim of the study was to determine if a more rational therapeutic approach could be devised for neuroleptic resistant psychotic patients treated for months and years with clozapine. Clozapine is an atypical antipsychotic medication, but its therapeutic benefit has been limited by a high incidence of agranulocytosis and seizures. 2. The study has been performed in an open setting and included 12 patients. Some of them developed a secondary depression and were treated with fluoxetine. 3. Pharmacokinetic analysis were conducted at the same time as clinical evaluations, grading using the BPRS, the PDS, and QLS, and determinations of plasma and red blood cell clozapine and desmethylclozapine, plasma and RBC fluoxetine and norfluoxetine, whole blood serotonin and tryptophan. 4. A positive linear correlation was found only between RBC concentration and the evolution of the QLS. 5. Clozapine is efficacious both on positive and negative symptoms but its mechanism of action remains unclear. Positive symptoms disappear more quickly, sometimes followed by a post psychotic depression. Negative symptoms improve more slowly but regularly. They seem to be correlated with serotoninergic mechanisms. For whole blood 5HT, an important increase was seen about 4 weeks after Cloza administration, and then a decrease. 6. Therapeutic drug monitoring (on the same sample drawn for haematological monitoring providing) could play a useful role in the management of patients treated by clozapine: compliance, lowest dose, possible toxicity, drug interaction, lack of efficacy, relapse predictivity.
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PMID:Pharmacoclinical strategy in neuroleptic resistant schizophrenic patients treated by clozapine: clinical evolution, concentration of plasma and red blood cell clozapine and desmethylclozapine, whole blood serotonin and tryptophan. 1036 54

Suicide is one of the most serious of schizophrenic symptoms and claims the life of 9% to 13% of patients. The annual rate of suicide in schizophrenic patients is reported to be in the range of 0.4% to 0.8%, a rate that has remained constant despite the introduction of antipsychotic therapy and attendant case-management systems. The risk of suicide is not significantly different in neuroleptic-resistant or -responsive schizophrenic patients. A study of 421 schizophrenic patients reported no significant difference in the incidence of lifetime and current episodes of suicidality in treatment-resistant and -responsive patients. A number of studies with clozapine, an atypical antipsychotic, have demonstrated an 80% to 85% reduction in suicide in neuroleptic-resistant patients. This is accompanied by a decrease in depression and psychopathology and improved cognition. Clozapine's modulation of serotonergic, noradrenergic, cholinergic, and dopamine function may be the biological basis for the reduction in suicide. Weekly contact with patients, for white blood cell monitoring, has also been put forward as one explanation. To further confirm suicide risk reduction as a benefit of clozapine therapy, the International Clozaril/Leponex Suicide Prevention Trial (InterSePT) is currently being conducted. This large, prospective treatment study will compare the rate of suicide attempts and completions in schizophrenic patients at high risk of suicide randomly assigned to receive clozapine or olanzapine. The bias of weekly visits will be excluded. Results should be available in 2001.
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PMID:Suicide and schizophrenia: clozapine and the InterSePT study. International Clozaril/Leponex Suicide Prevention Trial. 1037 12

The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (< 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.
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PMID:Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group. 1050 85

The pharmacology, efficacy, and adverse effects of atypical antipsychotic agents when used to treat schizophrenia and other disorders are reviewed. Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms, and troublesome adverse effects, especially extrapyramidal symptoms (EPSs) and tardive dyskinesia CTD). Atypical antipsychotics differ from typical psychotics in their "limbic-specific" dopamine type 2 (D2)-receptor binding and high ratio of serotonin type 2 (5-HT2)-receptor binding to D2 binding. In clinical trials in patients with non-treatment-resistant schizophrenia, risperidone and olanzapine were superior to placebo for positive and negative symptoms. Risperidone and olanzapine were superior to haloperidol on some measures. Quetiapine was better than placebo but was not better than typical antipsychotics. Head-to-head comparisons of atypical antipsychotics in non-treatment-resistant schizophrenia have been inconclusive. Clozapine remains the standard agent for treatment-resistant schizophrenia. Atypical agents are substantially more expensive than their typical antipsychotic counterparts. To fully determine the overall efficiency of these drugs, other potential benefits, such as improved quality of life, need to be factored in. Atypical antipsychotics are associated with a decreased capacity to cause EPSs, TD, neuroleptic malignant syndrome, and hyperprolactinemia. Clozapine carries a risk of agranulocytosis; the white blood cell count must be monitored. Atypical antipsychotics are increasingly being used for indications other than schizophrenia, such as the management of aggression, mania, and depression. Atypical antipsychotics are often considered first-line agents for treating schizophrenia and are promising treatment alternatives for other psychiatric and neurologic conditions.
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PMID:Atypical antipsychotic agents: a critical review. 1067 77

The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.
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PMID:Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline. 1114 28


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