Evidence that clozapine directly interacts on the GABAB receptor

Wu, Ying; Blichowski, Monica; Daskalakis, Zafiris J.; Wu, Zhouyou; Liu, Chun C.; Cortez, Miguel A.; Snead, O. Carter

doi:10.1097/wnr.0b013e328349739b

Cited by 45 publications

(29 citation statements)

References 20 publications

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“…Patients treated with clozapine show increased SP duration relative to controls and patients treated with other antipsychotics, suggesting improved GABA B -mediated cortical inhibition may partially underlie the therapeutic benefits of this drug. 34,35 In support, a recent animal study found clozapine facilitates binding of GABA to GABA B receptors, 52 whereas a separate study found baclofen, another GABA B agonist, normalizes cortical network behavior in a mouse model of SCZ. 53 …”

Section: Gaba B -Mediated Inhibitionmentioning

confidence: 80%

Cortical Inhibition, Excitation, and Connectivity in Schizophrenia: A Review of Insights From Transcranial Magnetic Stimulation

Rogasch

Daskalakis

Fitzgerald

2013

Schizophrenia Bulletin

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Schizophrenia (SCZ) is a debilitating mental illness with an elusive pathophysiology. Over the last decade, theories emphasizing cortical dysfunction have received increasing attention to explain the heterogeneous symptoms experienced in SCZ. Transcranial magnetic stimulation (TMS) is a noninvasive form of brain stimulation that is particularly suited to probing the fidelity of specific excitatory and inhibitory neuronal populations in conscious humans. In this study, we review the contribution of TMS in assessing inhibitory and excitatory neuronal populations and their long-range connections in SCZ. In addition, we discuss insights from combined TMS and electroencephalography into the functional consequences of impaired excitation/ inhibition on cortical oscillations in SCZ.

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Section: Gaba B -Mediated Inhibitionmentioning

confidence: 80%

Cortical Inhibition, Excitation, and Connectivity in Schizophrenia: A Review of Insights From Transcranial Magnetic Stimulation

Rogasch

Daskalakis

Fitzgerald

2013

Schizophrenia Bulletin

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“…Antipsychotic-induced somnolence can be due to a direct effect of blocking H 1 and other receptors or by acting on other neurotransmitter systems. Clozapine has been reported to directly interact with GABA receptors [102]. Zotepine activated neuronal activities in different regions of the brain and increased the extracellular levels of noradrenaline, dopamine, GABA, and glutamate in the prefrontal cortex [103].…”

Section: Interactions Among Receptorsmentioning

confidence: 99%

Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management

et al. 2016

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Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition. According to the ARI in acute schizophrenia, bipolar mania, and bipolar depression, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The risk of somnolence with blonanserin, brexpiprazole, chlorpromazine, iloperidone, sertindole, and zotepine needs further investigation. The rates of somnolence were positively correlated to dose and duration for some antipsychotics, but not for others. Many factors, including antipsychotic per se, the method used to measure somnolence, patient population, study design, and dosing schedule, might affect the incidence of antipsychotic-induced somnolence. The mechanisms of antipsychotic-induced somnolence are likely multifactorial, although the blockade of histamine 1 receptors and α1 receptors may play a major role. The management of antipsychotic-induced somnolence should include sleep hygiene education, choosing an antipsychotic with a lower risk for somnolence, starting at a lower dose with a slower titration based on psychiatric diagnoses, adjusting doses when necessary, and minimizing concurrent somnolence-prone agents. Since most cases of somnolence were mild to moderate, allowing tolerance to develop over at least 4 weeks is reasonable before discontinuing an antipsychotic.

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“…These findings suggest that clozapine potentiates the GABA B receptor and also underscores the possibility that the GABA B receptor may play a key role in the treatment of SCZ. Furthermore, a recent in-vivo study by Wu et al also confirmed these findings [10] which reported that the binding of the GABA B receptor antagonist 3 H]-CGP54626A increased when treated with clozapine. There was a significant correlation between the clozapine dose and the increase of 3 H]-CGP54626A binding in linear regression analysis.…”

Section: Introductionmentioning

confidence: 53%

Activation of GABAB receptors inhibits protein kinase B /Glycogen Synthase Kinase 3 signaling

Liu

et al. 2012

Mol Brain

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Accumulated evidence has suggested that potentiation of cortical GABAergic inhibitory neurotransmission may be a key mechanism in the treatment of schizophrenia. However, the downstream molecular mechanisms related to GABA potentiation remain unexplored. Recent studies have suggested that dopamine D2 receptor antagonists, which are used in the clinical treatment of schizophrenia, modulate protein kinase B (Akt)/glycogen synthase kinase (GSK)-3 signaling. Here we report that activation of GABAB receptors significantly inhibits Akt/GSK-3 signaling in a β-arrestin-dependent pathway. Agonist stimulation of GABAB receptors enhances the phosphorylation of Akt (Thr-308) and enhances the phosphorylation of GSK-3α (Ser-21)/β (Ser-9) in both HEK-293T cells expressing GABAB receptors and rat hippocampal slices. Furthermore, knocking down the expression of β-arrestin2 using siRNA abolishes the GABAB receptor-mediated modulation of GSK-3 signaling. Our data may help to identify potentially novel targets through which GABAB receptor agents may exert therapeutic effects in the treatment of schizophrenia.

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Evidence that clozapine directly interacts on the GABAB receptor

Cited by 45 publications

References 20 publications

Cortical Inhibition, Excitation, and Connectivity in Schizophrenia: A Review of Insights From Transcranial Magnetic Stimulation

Cortical Inhibition, Excitation, and Connectivity in Schizophrenia: A Review of Insights From Transcranial Magnetic Stimulation

Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management

Activation of GABAB receptors inhibits protein kinase B /Glycogen Synthase Kinase 3 signaling

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