Betahistine effects on weight-related measures in patients treated with antipsychotic medications: a double-blind placebo-controlled study

Smith, Robert C.; Maayan, Lawrence; Wu, Renrong; Youssef, Mary; Zhihui, Jing; Sershen, Henry; Szabo, Victoria; Meyers, Jordan; Jin, Hua; Zhao, Jinping; Davis, John M.

doi:10.1007/s00213-018-5079-1

Cited by 29 publications

(17 citation statements)

References 23 publications

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“…Therefore, future studies should investigate the role of the H1 receptor in regulating mTOR and calcium influx. Furthermore, it has been reported that activation of the hypothalamic H1 receptor, such as by using betahistine (an H1 receptor agonist/H3 receptor antagonist), reduced olanzapine-induced food intake and weight gain in rodents and patients ( Deng et al, 2012 ; Poyurovsky et al, 2013 ; Barak et al, 2016 ; Smith et al, 2018 ). Besides counteracting obesity, perhaps activating the H1 receptor by using betahistine, or another H1 receptor agonist, could also inhibit NLRP3/caspase-1 signaling and thus pyroptosis and brain volume loss induced by chronic antipsychotic treatment.…”

Section: Discussionmentioning

confidence: 99%

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

Fan

Zhou

et al. 2022

Front. Aging Neurosci.

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Emerging data indicate that antipsychotic treatment causes brain volume loss and astrocyte death, but the mechanisms remain elusive. Pyroptosis, inflammatory cell death characterized by the formation of inflammatory bodies, increased expression of nod-like receptor proteins (NLRPs) such as NLRP3, and activation of caspases and gasdermin D (GSDMD) are largely associated with innate immunity, inflammation, and cell injury/death. However, the main effect of antipsychotics on astrocyte pyroptotic signaling and the molecular mechanisms remain obscure. In the present study, 72-h treatment with olanzapine, quetiapine, risperidone, or haloperidol significantly decreased the viability of astrocytes. Twenty-four hour treatment with olanzapine, quetiapine, risperidone, or haloperidol dose-dependently increased the protein expression of astrocytic NLRP3, NLRP6, caspase-1, caspase-4, and GSDMD. Co-treatment with a histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine (FMPH), dose-dependently reduced the increased expression of NLRP3, caspase-1 and GSDMD induced by olanzapine, quetiapine, risperidone, or haloperidol. Moreover, olanzapine, quetiapine, risperidone, or haloperidol treatment induced pore formation in the membranes of astrocytes, and these effects were inhibited by FMPH co-treatment. Taken together, antipsychotic treatment activated astrocyte pyroptotic signaling, and these effects may be related to antipsychotic-induced astrocyte death. H1 receptor activation is an effective treatment strategy to suppress antipsychotic-induced astrocyte pyroptosis and inflammation.

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Section: Discussionmentioning

confidence: 99%

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

Fan

Zhou

et al. 2022

Front. Aging Neurosci.

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“…For instance, clozapine acts on H3 auto-receptors (with moderate affinity) to block acetylcholine (ACh) and noradrenaline (NA) release, resulting in dysregulation of appetite (62). Other reports support the involvement of H1 and H3 receptors in antipsychotic-induced weight gain and food intake (63,64). For instance, betahistine (a potent H1 and H3 agonist) has been combined with APDs (olanzapine/clozapine) and has been found to reduce APD-induced food intake and obesity both in rodents and humans through the H1R-NPY and the H1R-pAMPKα pathways (65)(66)(67).…”

Section: M3mentioning

confidence: 99%

Understanding the Effects of Antipsychotics on Appetite Control

et al. 2022

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Antipsychotic drugs (APDs) represent a cornerstone in the treatment of schizophrenia and other psychoses. The effectiveness of the first generation (typical) APDs are hampered by so-called extrapyramidal side effects, and they have gradually been replaced by second (atypical) and third-generation APDs, with less extrapyramidal side effects and, in some cases, improved efficacy. However, the use of many of the current APDs has been limited due to their propensity to stimulate appetite, weight gain, and increased risk for developing type 2 diabetes and cardiovascular disease in this patient group. The mechanisms behind the appetite-stimulating effects of the various APDs are not fully elucidated, partly because their diverse receptor binding profiles may affect different downstream pathways. It is critical to identify the molecular mechanisms underlying drug-induced hyperphagia, both because this may lead to the development of new APDs, with lower appetite-stimulating effects but also because such insight may provide new knowledge about appetite regulation in general. Hence, in this review, we discuss the receptor binding profile of various APDs in relation to the potential mechanisms by which they affect appetite.

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“…Many APs are antagonists at the H1 receptor, especially those with high propensity to cause AIWG. To our knowledge, only one study (296) has included pediatric patients (n = 12 of 51 total patients, age range [12][13][14][15][16][17]. In this sample, betahistine tempered weight gain in participants receiving the strongly antihistaminergic APs olanzapine and clozapine, but not for those taking other APs with lower H1 potency.…”

Section: Betahistinementioning

confidence: 99%

The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children

Libowitz

Nurmi

2021

Front. Psychiatry

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Antipsychotic medications are critical to child and adolescent psychiatry, from the stabilization of psychotic disorders like schizophrenia, bipolar disorder, and psychotic depression to behavioral treatment of autism spectrum disorder, tic disorders, and pediatric aggression. While effective, these medications carry serious risk of adverse events—most commonly, weight gain and cardiometabolic abnormalities. Negative metabolic consequences affect up to 60% of patients and present a major obstacle to long-term treatment. Since antipsychotics are often chronically prescribed beginning in childhood, cardiometabolic risk accumulates. An increased susceptibility to antipsychotic-induced weight gain (AIWG) has been repeatedly documented in children, particularly rapid weight gain. Associated cardiometabolic abnormalities include central obesity, insulin resistance, dyslipidemia, and systemic inflammation. Lifestyle interventions and medications such as metformin have been proposed to reduce risk but remain limited in efficacy. Furthermore, antipsychotic medications touted to be weight-neutral in adults can cause substantial weight gain in children. A better understanding of the biological underpinnings of AIWG could inform targeted and potentially more fruitful treatments; however, little is known about the underlying mechanism. As yet, modest genetic studies have nominated a few risk genes that explain only a small percentage of the risk. Recent investigations have begun to explore novel potential mechanisms of AIWG, including a role for gut microbiota and microbial metabolites. This article reviews the problem of AIWG and AP metabolic side effects in pediatric populations, proposed mechanisms underlying this serious side effect, and strategies to mitigate adverse impact. We suggest future directions for research efforts that may advance the field and lead to improved clinical interventions.

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Betahistine effects on weight-related measures in patients treated with antipsychotic medications: a double-blind placebo-controlled study

Cited by 29 publications

References 23 publications

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

Understanding the Effects of Antipsychotics on Appetite Control

The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children

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