Clozapine and Agranulocytosis

Idänpään-Heikkilä, J; Alhava, Eeva; Olkinuora, M.; Palva, I. P.

doi:10.1016/s0140-6736(75)90206-8

Cited by 156 publications

(73 citation statements)

References 5 publications

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“…Due to the potential risk of neutropenia observed with this drug, leukocyte counts were performed weekly during the trial period in every patient (1, 14).…”

Section: Methodsmentioning

confidence: 99%

Modulatory effect of clozapine on levodopa response in parkinson's disease: A preliminary study

Arevalo

Gershanik

1993

Movement Disorders

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Clozapine has been shown not only to be effective in ameliorating dopaminomimetic psychosis but to improve parkinsonian symptomatology. Six parkinsonian patients with motor fluctuations under levodopa treatment and severe interdose "off" periods (believed to be mediated by an inhibitory effect of subthreshold levels of levodopa) underwent a trial of clozapine. The effects of this drug on levodopa response were measured by means of an acute levodopa test both before and after receiving clozapine. After 1 month of treatment, clozapine 25 mg/day reduced parkinsonian scores at all stages of the evaluation (pre-levodopa "off," "on," and interdose "off"). The effect was consistently more significant for the interdose "off." Clozapine could be exerting its beneficial effects through the inhibition of an inhibitory effect mediated by low-level dopaminergic stimulation, thus behaving as an apparent anti-parkinsonian drug.

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“…Due to the potential risk of neutropenia observed with this drug, leukocyte counts were performed weekly during the trial period in every patient (1, 14).…”

Section: Methodsmentioning

confidence: 99%

Modulatory effect of clozapine on levodopa response in parkinson's disease: A preliminary study

Arevalo

Gershanik

1993

Movement Disorders

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“…Quetiapine was selected for studies in normal subjects based on our past experience (Wasserman et al, 2002), lack of association with rare but severe side effects observed with other atypical antipsychotics (Idanpaan-Heikkila et al, 1975;Wirshing et al, 1998), and 'clozapine-like' profile in preclinical studies of PPI (Swerdlow et al, 1994b(Swerdlow et al, , 1996. Analyses attempted to identify correlates or predictors of quetiapine effects on PPI in normal subjects with a 'low PPI' trait.…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats

Swerdlow

Talledo

Sutherland

et al. 2006

Neuropsychopharmacol

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Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg po) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals o120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.

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“…In addition, clozapine has been reported to be more effective than conventional antipsychotic drugs in reducing symptoms of patients with both treatment-resistant and non-resistant schizophrenia [2], suicide prevention [3], as well as remission of heavy cigarette smoking [4]. However, since the report of fatal agranulocytosis in patients treated with clozapine in 1975 [5], the use of clozapine has been limited only to patients with refractory schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

et al. 2006

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Aims/hypothesis Diabetogenic effects of some atypical antipsychotic drugs have been reported, although the mechanisms are not fully understood. We investigated the long-term effects of culturing isolated rat pancreatic islets with atypical antipsychotic clozapine. Methods Glucose-and non-glucose-stimulated insulin secretion, glucose metabolism and intracellular Ca 2+ concentration ([Ca 2+ ] i ) were measured in islets cultured with or without clozapine. Results Although acute incubation or 3-day culture with clozapine did not affect glucose-stimulated insulin secretion, clozapine suppressed glucose-stimulated insulin secretion by 53.2% at 1.0 μmol/l (therapeutic concentration) after 7 days of culture. Islet glucose oxidation and [Ca 2+ ] i elevation by high glucose were not affected after 3 days of culture, but clozapine significantly inhibited islet glucose oxidation, ATP production, and [Ca 2+ ] i elevation by high glucose after 7 days of culture. Moreover, 7 days of culture with clozapine inhibited insulin secretion stimulated by: (1) membrane depolarisation induced by high K + ; (2) protein kinase C activation; and (3) mastoparan at 16.7 mmol/l glucose under stringent Ca 2+ -free conditions. Elevation of [Ca 2+ ] i by high K + -induced membrane depolarisation was similar in control and clozapine-treated islets. Clozapine, a muscarinic blocker, acutely inhibited carbachol-induced insulin secretion, as did atropine, whereas after 7 days of culture atropine did not have the inhibitory effect shown by clozapine after 7 days. The impairment of glucose-stimulated insulin secretion recovered 3 days after the removal of clozapine treatment. Conclusions/interpretationThe present study demonstrated that the atypical antipsychotic drug clozapine directly impaired insulin secretion via multiple sites including glucose metabolism and the distal step in insulin exocytosis in a long-term culture condition. These mechanisms may be involved in the form of diabetes mellitus associated with atypical antipsychotic drugs.

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Clozapine and Agranulocytosis

Cited by 156 publications

References 5 publications

Modulatory effect of clozapine on levodopa response in parkinson's disease: A preliminary study

Modulatory effect of clozapine on levodopa response in parkinson's disease: A preliminary study

Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

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