EEG alterations in patients treated with clozapine in relation to plasma levels

Haring, C.; Neudorfer, C.; Schett, P.; Schwitzer, Josef; Saria, Alois; Hummer, Martina; Fleischhacker, W. Wolfgang

doi:10.1016/0920-9964(92)90177-7

Cited by 13 publications

(19 citation statements)

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“…Thus, the results of previous studies [7,13] were reproduced on a quantitative level. However, we did not find any dose-related increase of slow-wave activity.…”

Section: Discussionmentioning

confidence: 91%

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Clozapine in Patients with Chronic Schizophrenia: Serum Level, EEG and Memory Performance

Adler

Grieshaber²,

Faude³

et al. 2002

Pharmacopsychiatry

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The atypical antipsychotic clozapine causes EEG alterations, and may lead to memory impairments due to its anticholinergic properties. The relationships between clozapine serum level, quantitative EEG parameters and performance in vigilance and memory tasks were studied in a group of 17 chronically ill schizophrenic patients under maintenance treatment with clozapine at stable dosages. There were negative correlations between clozapine serum levels and the amount of high-frequency EEG activity and positive correlations between high-frequency EEG activity and memory performance. These findings may suggest that clozapine treatment brings about dose-dependent impairments of vigilance and memory, for which a reduction of high-frequency EEG activity is indicative.

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“…Thus, the results of previous studies [7,13] were reproduced on a quantitative level. However, we did not find any dose-related increase of slow-wave activity.…”

Section: Discussionmentioning

confidence: 91%

“…The degree of EEG changes depends on the clozapine serum level [7,13]. EEG slowing under clozapine treatment may be related to drug-induced memory impairments analogous to the memory impairments in Alzheimer's disease, which are attributed to cholinergic deficit and are correlated with a decrease in high-frequency EEG activity [15].…”

Section: Introductionmentioning

confidence: 98%

Clozapine in Patients with Chronic Schizophrenia: Serum Level, EEG and Memory Performance

Adler

Grieshaber²,

Faude³

et al. 2002

Pharmacopsychiatry

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“…It coincides with prolonged high-dose therapy (Devinsky et al 1991;Pacia and Devinsky 1994), when clozapine concentrations in blood plasma (and presumably those in the brain; see: Hartvig et al 1986) are elevated to micromolar levels (Choc et al 1987;Hating et al 1994), or with a rapid titration phase at low doses especially in patients with a history of seizures or epilepsy (Pacia and Devinsky 1994). This mechanism cannot account for the proconvulsive properties of neuroleptic drugs generally (Messing et al 1984), since haloperidol failed to antagonize G A B A at micromolar concentrations ( Fig.…”

Section: Clozapine As a Gabaa Antagonistmentioning

confidence: 99%

Subtype specificity of ?-aminobutyric acid type A receptor antagonism by clozapine

Korpi¹,

Wong²,

Lüddens

1995

Naunyn-Schmiedeberg's Arch Pharmacol

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Clozapine, an atypical neuroleptic, functionally antagonizes the gamma-aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, gamma-aminobutyric acid type A (GABAA) receptor, in brain vesicles. GABAA antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABAA antagonist 2'-(3'-carboxy-2',3'-propyl)-3-amino-6-p -methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [35S]TBPS binding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [3H]muscimol and [3H]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [35S]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [35S]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas where its antagonism was greater than average. Recombinant alpha 6 beta 2 gamma 2 receptors, the predominant alpha 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism by clozapine up to 100 microM. In contrast, recombinant alpha 1 beta 2 gamma 2 receptors, forming the predominant receptor subtype in the brain, were clozapine sensitive. Recombinant alpha 6 beta 2 gamma 2 and alpha 6 beta 3 gamma 2 receptors resulted in clozapine-insensitive receptors, whereas alpha 6 beta 1 gamma 2 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in alpha 1 beta x gamma 2 receptors decreased in the order of alpha 1 beta 1 gamma 2 > alpha 1 beta 2 gamma 2> alpha 1 beta 3 gamma 2. The results indicate that clozapine antagonizes the function of most GABAA receptor subtypes, and that the interaction is determined by the interaction of the alpha and beta subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment.

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“…First, Liu et al (1996) reported that clinical improvement is reduced with plasma clozapine levels beyond 700 ng/ml. Second, side effects such as abnormal electroencephalograms (EEG) (Haring et al 1994;Freudenreich et al 1997), sedation (VanderZwaag et al 1996), and orthostatic hypotension (Ackenheil et al 1989) have been correlated with plasma clozapine levels. Therefore, raising plasma levels also increases the risk of adverse events.…”

Section: Discussionmentioning

confidence: 99%