Developed catatonia with rhabdomyolysis and exacerbated cardiac failure upon switching from clozapine to olanzapine owing to cardiomyopathy during clozapine medication - A case report

Ito, Yuki; Murata, Masahiko; Omori, Taku; Fukuyama, Kouji; Motomura, Eishi; Dohi, Kaoru; Okada, Motohiro

doi:10.1016/j.ajp.2022.103376

Cited by 5 publications

(3 citation statements)

References 18 publications

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“…Conversely, a portion of the pathophysiology of clozapine-discontinuation syndrome could also be explained by the effects of clozapine on L-BAIBA. Prompt clozapine discontinuation due to several clinical scenarios, i.e., severe type B reactions or voluntary discontinuation by patients, can precipitate the sudden emergence of psychotic symptoms, which have been termed "clozapine-discontinuation syndrome" [9,10,89,90]. Clozapinediscontinuation catatonia is considered to be one of the worst prognoses in catatonic syndrome, due to the high prevalence of comorbid of rhabdomyolysis and benzodiazepine resistance [10,[89][90][91].…”

Section: Discussionmentioning

confidence: 99%

“…Prompt clozapine discontinuation due to several clinical scenarios, i.e., severe type B reactions or voluntary discontinuation by patients, can precipitate the sudden emergence of psychotic symptoms, which have been termed "clozapine-discontinuation syndrome" [9,10,89,90]. Clozapinediscontinuation catatonia is considered to be one of the worst prognoses in catatonic syndrome, due to the high prevalence of comorbid of rhabdomyolysis and benzodiazepine resistance [10,[89][90][91]. These distinct symptomatic features of clozapine-discontinuation catatonia, such as benzodiazepine resistance, suggest that the pathophysiology of clozapinediscontinuation catatonia is involved in different mechanisms compared to other catatonic syndromes, such as idiopathic lethal catatonia, benzodiazepine-withdrawal catatonia, and neuroleptic malignant syndrome, possibly induced by the dysfunction of GABA B -R [9,10,51,91,92].…”

Section: Discussionmentioning

confidence: 99%

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Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine

2023

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Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of clozapine remain to be elucidated. Recently, we demonstrated that clozapine increased the synthesis of L-β-aminoisobutyric acid (L-BAIBA) in the hypothalamus. L-BAIBA is an activator of the adenosine monophosphate-activated protein kinase (AMPK), glycine receptor, GABAA receptor, and GABAB receptor (GABAB-R). These targets of L-BAIBA overlap as potential targets other than the monoamine receptors of clozapine. However, the direct binding of clozapine to these aminoacidic transmitter/modulator receptors remains to be clarified. Therefore, to explore the contribution of increased L-BAIBA on the clinical action of clozapine, this study determined the effects of clozapine and L-BAIBA on tripartite synaptic transmission, including GABAB-R and the group-III metabotropic glutamate receptor (III-mGluR) using cultured astrocytes, as well as on the thalamocortical hyper-glutamatergic transmission induced by impaired glutamate/NMDA receptors using microdialysis. Clozapine increased astroglial L-BAIBA synthesis in time/concentration-dependent manners. Increased L-BAIBA synthesis was observed until 3 days after clozapine discontinuation. Clozapine did not directly bind III-mGluR or GABAB-R, whereas L-BAIBA activated these receptors in the astrocytes. Local administration of MK801 into the reticular thalamic nucleus (RTN) increased L-glutamate release in the medial frontal cortex (mPFC) (MK801-evoked L-glutamate release). Local administration of L-BAIBA into the mPFC suppressed MK801-evoked L-glutamate release. These actions of L-BAIBA were inhibited by antagonists of III-mGluR and GABAB-R, similar to clozapine. These in vitro and in vivo analyses suggest that increased frontal L-BAIBA signaling likely plays an important role in the pharmacological actions of clozapine, such as improving the effectiveness of treating treatment-resistant schizophrenia and several clozapine discontinuation syndromes via the activation of III-mGluR and GABAB-R in the mPFC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine

2023

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“…These cognitive impairments are more suggestive of impaired function of glutamate transmission (via thalamocortical pathways) than monoamine transmission (via the mesolimbic and mesocortical systems). These cognitive impairment features of TRS suggest it may be caused by dysfunction of glutamatergic transmission (via thalamocortical pathways) rather than monoaminergic transmission (via mesolimbic and mesocortical pathways) [ 15 , 38 , 41 , 42 , 43 , 44 , 104 ].…”

Section: Clozapine and Trsmentioning

confidence: 99%

A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine

Fukuyama,

Motomura,

Okada

2023

Biomolecules

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Clozapine is listed as one of the most effective antipsychotics and has been approved for treating treatment-resistant schizophrenia (TRS); however, several type A and B adverse reactions, including weight gain, metabolic complications, cardiotoxicity, convulsions, and discontinuation syndromes, exist. The critical mechanisms of clinical efficacy for schizophrenia, TRS, and adverse reactions of clozapine have not been elucidated. Recently, the GABA isomer L-β-aminoisobutyric acid (L-BAIBA), a protective myokine in the peripheral organs, was identified as a candidate novel transmission modulator in the central nervous system (CNS). L-BAIBA activates adenosine monophosphate-activated protein kinase (AMPK) signalling in both the peripheral organs and CNS. Activated AMPK signalling in peripheral organs is an established major target for treating insulin-resistant diabetes, whereas activated AMPK signalling in the hypothalamus contributes to the pathophysiology of weight gain and metabolic disturbances. Clozapine increases L-BAIBA synthesis in the hypothalamus. In addition, the various functions of L-BAIBA in the CNS have recently been elucidated, including as an activator of GABA-B and group-III metabotropic glutamate (III-mGlu) receptors. Considering the expressions of GABA-B and III-mGlu receptors (localised in the presynaptic regions), the activation of GABA-B and III-mGlu receptors can explain the distinct therapeutic advantages of clozapine in schizophrenia or TRS associated with N-methyl-D-aspartate (NMDA) receptor disturbance compared with other atypical antipsychotics via the inhibition of the persistent tonic hyperactivation of thalamocortical glutamatergic transmission in the prefrontal cortex. L-BAIBA has also been identified as a gliotransmitter, and a detailed exploration of the function of L-BAIBA in tripartite synaptic transmission can further elucidate the pathophysiology of effectiveness for treating TRS and/or specific adverse reactions of clozapine.

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Antipsychotics/mood-stabilisers

2023

Reactions Weekly

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Developed catatonia with rhabdomyolysis and exacerbated cardiac failure upon switching from clozapine to olanzapine owing to cardiomyopathy during clozapine medication - A case report

Cited by 5 publications

References 18 publications

Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine

Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine

A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine

Antipsychotics/mood-stabilisers

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