High-Dose Betahistine Improves Cognitive Function in Patients With Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Wang, Yongqian; Huang, Xu‐Feng; Fan, Hongzhen; An, Huimei; Ma, Ting; Zhang, Qi; Zhao, Weihua; Yun, Yajun; Yang, Wenshuang; Zhang, Xiaolu; Wang, Zhiren; Yang, Fude

doi:10.3389/fpsyt.2021.762656

Cited by 6 publications

(7 citation statements)

References 35 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 13 Betahistine , an H1 receptor agonist and H3 receptor antagonist, enhanced cognitive function in schizophrenic patients. 14 Lorcaserin and betahistine have also been reported to decrease food intake and promote weight loss in animals and humans. 9 , 12 , 15 , 16 Notably, H3 receptor antagonists have been shown to increase extracellular dopamine concentrations in the prefrontal cortex.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hypothesis: Amelioration of obesity‐induced cognitive dysfunction via a lorcaserin–betahistine combination treatment

Peña

Figueroa

Shi

2022

Pharmacology Res & Perspec

View full text Add to dashboard Cite

The prolonged exposure to obesogenic diets disrupts the mesocortical dopaminergic input to the prefrontal cortex (PFC). This leads to suboptimal dopamine levels in this brain region, which affects cognition and control of food intake. Treatments that restore mesocortical dopaminergic neurotransmission may improve obesity‐associated cognitive dysfunction and modulate food intake to induce weight loss. Given the complexity and multifactorial nature of obesity, combination treatments would likely achieve sizeable and sustained body weight loss and improve obesity‐linked outcomes, such as cognitive dysfunction. Given this background, we hypothesize that concomitant activation of serotonin 5‐HT2C and histamine H1 receptors, coupled with antagonism of histamine H3 receptors, synergistically modulates mesocortical dopamine neurotransmission and ameliorates obesity‐induced cognitive dysfunction. We propose to test the hypothesis in a diet‐induced obesity (DIO) rat model by treating animals with the 5‐HT2C agonist lorcaserin and the H1 agonist and H3 antagonist betahistine. Consistent with our hypothesis, both lorcaserin and betahistine have been shown to reduce body weight in humans with obesity and animals. Both drugs have been demonstrated to improve cognitive functions by influencing dopaminergic signaling in the PFC. The proposed combination treatment addresses the paucity of studies on obesity treatments that improve cognitive function. This research may also help identify a potential targetable mechanism connecting obesity and neurocognitive outcomes.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Lorcaserin also improved the cognitive functions of obese animals 13 Betahistine,. an H1 receptor agonist and H3 receptor antagonist, enhanced cognitive function in schizophrenic patients 14 . Lorcaserin and betahistine have also been reported to decrease food intake and promote weight loss in animals and humans 9,12,15,16 …”

Section: Introductionmentioning

confidence: 99%

Hypothesis: Amelioration of obesity‐induced cognitive dysfunction via a lorcaserin–betahistine combination treatment

Peña

Figueroa

Shi

2022

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…The findings that we report, together with existing evidence of lower ACC glutamate levels being associated with impaired cognition, suggest that H3R antagonism in patients with schizophrenia may improve cognitive impairment, which is a feature of the disorder, by increasing glutamate transmission. Consistent with this, betahistine (H1R agonist/H3R antagonist) has been found to improve cognitive symptoms ( Wang et al, 2021 ). However, H3R-specific compounds have shown mixed results in treating cognitive impairment associated with schizophrenia in clinical trials ( Vohora and Bhowmik, 2012 ; Egan et al, 2013 ; Haig et al, 2014 ; Jarskog et al, 2015 ).…”

Section: Discussionmentioning

confidence: 63%

Histamine-3 Receptor Availability and Glutamate Levels in the Brain: A PET-1H-MRS Study of Patients With Schizophrenia and Healthy Controls

Arumuham,

Nour,

Veronese

et al. 2024

International Journal of Neuropsychopharmacology

View full text Add to dashboard Cite

Background The histamine-3 receptor (H3R) may have a role in cognitive processes, through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia, and characterised their relationships with glutamate levels in corresponding brain regions. Methods We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography (PET) using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest (ROIs). Results We found significant inverse relationships between tracer uptake and Glu (r = -0.66, p = 0.02) and Glx (r = -0.62, p = 0.04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, p = 0.56, Glx: r = 0.10, p = 0.75). We also found a significant difference in striatal (F1,20 = 6.00, p = 0.02) and ACC (F1,19 = 4.75, p = 0.04) Glx levels between groups. Conclusions These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing pre-clinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signalling.

show abstract

“…Finally, more broadly, these findings may also have an impact on the treatment of other diseases with betahistine. For instance, in high dosages it can improve cognition in schizophrenia ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Examination of betahistine bioavailability in combination with the monoamine oxidase B inhibitor, selegiline, in humans—a non-randomized, single-sequence, two-period titration, open label single-center phase 1 study (PK-BeST)

Strupp,

Churchill,

Naumann

et al. 2023

Front. Neurol.

View full text Add to dashboard Cite

BackgroundBetahistine was registered in Europe in the 1970s and approved in more than 80 countries as a first-line treatment for Menière's disease. It has been administered to more than 150 million patients. However, according to a Cochrane systematic review of betahistine and recent meta-analyses, there is insufficient evidence to say whether betahistine has any effect in the currently approved dosages of up to 48 mg/d. A combination with the monoamine oxidase B (MAO-B) inhibitor, selegiline, may increase the bioavailability of betahistine to levels similar to the well-established combination of L-DOPA with carbidopa or benserazide in the treatment of Parkinson's disease. We investigated the effect of selegiline on betahistine pharmacokinetics and the safety of the combination in humans.MethodsIn an investigator-initiated prospective, non-randomized, single-sequence, two-period titration, open label single-center phase 1 study, 15 healthy volunteers received three single oral dosages of betahistine (24, 48, and 96 mg in this sequence with at least 2 days' washout period) without and with selegiline (5 mg/d with a loading period of 7 days). Betahistine serum concentrations were measured over a period of 240 min at eight time points (area under the curve, AUC0-240 min). This trial is registered with EudraCT (2019-002610-39) and ClinicalTrials.gov.FindingsIn all three single betahistine dosages, selegiline increased the betahistine bioavailability about 80- to 100-fold. For instance, the mean (±SD) of the area under curve for betahistine 48 mg alone was 0.64 (+/-0.47) h*ng/mL and for betahistine plus selegiline 53.28 (+/-37.49) h*ng/mL. The half-life time of around 30 min was largely unaffected, except for the 24 mg betahistine dosage. In total, 14 mild adverse events were documented.InterpretationThis phase 1 trial shows that the MAO-B inhibitor selegiline increases betahistine bioavailability by a factor of about 80 to 100. No safety concerns were detected. Whether the increased bioavailability has an impact on the preventive treatment of Menière's disease, acute vestibular syndrome, or post-BPPV residual dizziness has to be evaluated in placebo-controlled trials.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05938517?intr=betahistine%20and%20selegiline&rank=1, identifier: NCT05938517.

show abstract

High-Dose Betahistine Improves Cognitive Function in Patients With Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Cited by 6 publications

References 35 publications

Hypothesis: Amelioration of obesity‐induced cognitive dysfunction via a lorcaserin–betahistine combination treatment

Hypothesis: Amelioration of obesity‐induced cognitive dysfunction via a lorcaserin–betahistine combination treatment

Histamine-3 Receptor Availability and Glutamate Levels in the Brain: A PET-1H-MRS Study of Patients With Schizophrenia and Healthy Controls

Examination of betahistine bioavailability in combination with the monoamine oxidase B inhibitor, selegiline, in humans—a non-randomized, single-sequence, two-period titration, open label single-center phase 1 study (PK-BeST)

Contact Info

Product

Resources

About