Effects of Adjunctive Betahistine Therapy on Lipid Metabolism in Patients with Chronic Schizophrenia: A Randomized Double-Blind Placebo-Controlled Study

Introduction

Schizophrenia is a chronic psychiatric disorder with complex etiology and is associated with severe disease burden and high disability rate.¹ Epidemiological studies have shown that the prevalence of metabolic syndrome in patients with schizophrenia is 42.0%, which is approximately 2- to 3-fold higher than in general population.^2,3 Several large-scale meta-analyses confirmed that patients with schizophrenia have a significantly increased risk of lipid metabolism and lipid metabolism-related mortality, which may possibly increase over time,^4,5 warranting urgent clinical attention. Therefore, comprehensive prevention and treatment of lipid metabolic abnormalities is essential for patients diagnosed with schizophrenia.

Schizophrenia disease per se, obesity, antipsychotic use and adverse lifestyle are risk factors contributing to lipid metabolism in patients with schizophrenia.^6–8 A number of studies have reported that adjunctive medications can improve the metabolic abnormalities of patients with schizophrenia. These medications include metformin, GLP-1RAs, topiramate, sibutramine, aripiprazole, lorcaserin, orlistat, naltrexone, bupropion, amantadine, zonisamide, melatonin and betahistine.^9–16 Among them, betahistine, as a regulator of histamine system, has received widespread attention due to its excellent safety profile and unique pharmacological properties as a histaminergic H₁ receptor agonist and partial H₃ receptor antagonist. Betahistine was studied mainly as a vasodilator for conditions such as cluster headaches, vascular dementia and Meniere’s disease, but in recent years, it was found to be a key neurotransmitter in the regulation of feeding behavior.¹⁷ Some clinical trials reported that adjunctive betahistine therapy can inhibit weight gain or obesity caused by antipsychotics.^18–20 A possible strategy is to reduce food intake by regulating the histaminergic H1 receptor (H1R) - neuropeptide Y (NPY) - AMP-activated protein kinase (AMPK) pathway of the hypothalamus, increasing the thermogenic effect of brown adipose tissue.²¹ Another possible approach is to improve AMPK-SREBP-1-PPAR-related pathways in the liver to alleviate blood lipid abnormalities.¹⁷

However, using adjunctive betahistine therapy to treat lipid metabolic abnormalities in patients with schizophrenia is not supported by evidence-based medicine. Therefore, this randomized double-blind placebo-controlled study investigated the ability of betahistine to improve weight gain and abnormal lipid metabolism and thus provide evidence for early prevention and treatment of metabolic syndrome in patients with chronic schizophrenia.

Methods

Participants

A total of 94 inpatients with schizophrenia were recruited from Beijing Huilongguan Hospital between September 2019 and September 2021. Researchers fully notified all participants of the purpose and design of this study. All participants voluntarily signed informed consent forms.

All participants met the following inclusion criteria: (1) inpatient status and diagnosis of schizophrenia in accordance with the International Classification of Diseases (ICD)-10 criteria, (2) aged 18~65 years, (3) Han nationality, (4) disease course longer than 10 years and (5) current use of antipsychotics and relatively stable condition.

The exclusion criteria were as follows: (1) use of drugs that affect central nervous system and immune function during the study, (2) current or previous diagnosis of any other mental diseases, (3) history of alcohol or drug abuse within the previous 6 months, (4) pregnancy or lactation and (5) contraindications to betahistine.

Randomization and Blinding

Patients with schizophrenia (n = 94) were randomly assigned to the betahistine group or the placebo group using the PROC PLAN program of SAS package (SAS for Windows, Version 9.4, SAS Institute Inc., Cary, NC). The leader researcher generated a randomization table using block randomization with blocks of size 4, which was preserved by trial designer. Pharmacists participating in the study placed random numbers in envelopes marked with patient numbers. The envelope was left in the pharmacy and was only opened by the pharmacist when randomizing the study participants. Individuals directly involved in the study had no access to these envelopes. Betahistine or placebo was installed in a white opaque plastic bottle. The placebo was the same as betahistine in appearance, characteristics and size. Individuals involved in this study except the trial designer did not know whether betahistine or placebo was administered.

Pharmaceutical Source and Intervention Plan

Betahistine hydrochloride (Xinxiang LepuHengjiuyuan Pharmaceutical Co., Ltd., Henan, China) was used in this study; the specification was 4 mg/tablet. Patients in the betahistine group were administered 48 mg of betahistine hydrochloride per day (16 mg t.i.d.). Patients in the placebo group were given a placebo at the same frequency and dose as the betahistine group. Without affecting the original treatment, all participants were treated with an additional betahistine/placebo for 4 weeks.

Observation Index and Data Collection

This study used a self-made form to record the data of all the participants. The researchers measured participants’ height, weight, waist and hip circumference in the morning at baseline and 4 weeks after the intervention. BMI and waist-to-hip ratio (WHR) were calculated. The Positive and Negative Syndrome Scale (PANSS)²² was used to comprehensively evaluate the severity of psychiatric symptoms of patients with schizophrenia at baseline and 4 weeks after the intervention. The PANSS scale consists of seven positive symptom scores, seven negative symptom scores, and 16 general psychopathological symptom scores. Higher PANSS scores reflect more severe psychiatric symptoms. All researchers participating in the evaluation completed consistency training and the intraclass correlation coefficient (ICC) >0.75 between researchers.

At 7:00 h on the second day after baseline measurements, the venous blood (4 mL) was drawn from all the participants on an empty stomach and immediately centrifuged at 4°C and 3000 r/min for 10 min. The supernatant was transferred to an EP tube for storage at −80°C in a refrigerator until tested. Blood was drawn again from all the participants at 4 weeks after the intervention and processed similarly. Parameters of lipid metabolism analyzed in the blood samples included triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein a (Apo-A), apolipoprotein b (Apo-b) and lipoprotein (a) [LP (a)].

Safety Assessment

The Treatment Emergent Symptom Scale (TESS)²³ was used to comprehensively evaluate adverse effects of treatment at baseline and 4 weeks after the intervention. We defined “severity” greater than or equal to 1, and “relationship with drugs” as “possibly” a side effect of betahistine.

Statistical Analysis

Data analysis was based on intent-to-treat method, and the missing observations were treated using the last observation carried forward (LOCF). Statistical analysis was conducted using SPSS 25.0 software package. Quantitative data were expressed as mean ± standard deviation, and qualitative data were expressed as frequencies. Normality of the data was tested using the Shapiro–Wilk test. Comparisons between groups were made using the independent sample t-test when the data were normally distributed; otherwise, Wilcoxon rank-sum test was used as an alternative method. Categorical data were compared using the χ2 test. Repeated measures analysis of variance (ANOVA) was performed to analyze the differences in metabolism indicators of different groups over time. When the bilateral p value was <0.05, the difference was considered statistically significant.

Ethical Considerations

The trial was approved by the ethics committee of the Beijing Huilongguan Hospital (number: 2018–47) and registered at the China Clinical Test Center (CHICTR1900021078). This study was conducted according to the Declaration of Helsinki.

Results

Participants’ Characteristics

Two participants in betahistine group and three participants in placebo group were lost to follow-up due to discharge from hospital. Data at discharge were used to replace that at 4 weeks after the intervention. Betahistine group included 28 male and 19 female patients with schizophrenia, with an average age of 46.49 ± 9.00 years, and the average course of disease was 22.55 ± 10.71 years. Placebo group included 29 male and 18 female patients with schizophrenia, with an average age of 46.28 ± 10.17 years, and an average disease course of 22.13 ± 11.37 years. There was no significant difference with regard to types of antipsychotics between two groups (χ2 = 0.42, p = 0.667), and olanzapine was the most commonly used drugs (31.9% in betahistine group, 36.2% in placebo group, respectively). No statistically significant differences existed between two groups in gender, age, course, chlorpromazine equivalent and lipid metabolic indicators (p > 0.05) as shown in Table 1.

Table 1 Baseline Characteristics of Participants and Comparison Between Betahistine Group and Placebo Group

Efficacy Evaluation

The results of ANOVA showed that after 4 weeks of betahistine/placebo treatment, the interaction effect of time and group was statistically significant on LDL-C (F = 6.453, p = 0.013). A further simple effect analysis revealed that the time main effect of placebo group was significant (F = 5.602, p = 0.023), and the time main effect of betahistine group was not significant (F = 1.391, p = 0.245). No obvious time main effects were found in the two groups (F = 0.878, p = 0.351) and no obvious group differences were detected (F = 0.012, p = 0.912).

The interaction effect of time and group was statistically significant on WHR (F = 4.473, p = 0.037). No obvious time main effects were found in the two groups (F = 0.142, p = 0.708) and no obvious group differences were detected (F = 0.226, p = 0.636). After 4 weeks of treatment with betahistine/placebo, ANOVA did not reveal any significant interaction effect of time and group on weight, BMI and other lipid metabolic parameters, as well as the time main effect and group main effect (all p > 0.05), as shown in Table 2.

Table 2 Comparison of Weight and Lipid Metabolism in Betahistine Group and Placebo Group at Baseline and 4 Weeks

Psychiatric Symptoms

Changes in psychiatric symptoms after 4 weeks of intervention are shown in Table 3. There were no time-group effects involving positive symptom scores, negative symptom scores, general psychopathological symptom scores, or total scores in the betahistine group.

Table 3 Changes in Psychiatric Symptoms of Patients in Betahistine and Placebo Groups at Baseline and 4 Weeks Later

Adverse Effects

During the 4-week intervention, the TESS items in both betahistine and placebo groups were not greater than the “basic relationship.” Thus, all patients involved in this study showed no betahistine-related adverse effect. In the first week of treatment, a patient in betahistine group showed increased antipsychotic levels in the blood. A complete evaluation revealed that it had no basic relationship with betahistine.

Discussion

This study found no impact of betahistine on weight and BMI in patients with chronic schizophrenia, which is inconsistent with other studies reported previously. Lian et al²⁵ found that betahistine treatment in animal models showed reversal in olanzapine-induced body weight gain mediated via H1R-NPY and H1R-AMPK-alpha phosphorylation. Activation of H₁ receptors increased the amount of histamine released, causing a series of physiological reactions, weight reduction, and energy metabolism.²⁶ However, blocking H₃ receptor can indirectly enhance the role of H₁ receptor,²⁷ and H₁ receptor is the main cause of antipsychotic-induced weight gain/obesity. Barak et al²⁸ showed that after 4 weeks of treatment, the average weight increase in the betahistine group 37% less than in placebo group. Although the foregoing studies indicate that betahistine can reduce patients’ weight, other studies found that betahistine has no effect on weight. A proof-of-concept, randomized, double-blind, placebo-controlled, dose-ranging study was performed by Ali AH et al²⁹ to analyze the effects of betahistine on class I or II obesity in women. The results showed that after a 24-h placebo run-in period, 144 mg betahistine/d did not induce any effect on food intake or appetite. In a randomized, placebo-controlled, dual-center (China and the United States) study by Smith et al,³⁰ betahistine was significantly better than placebo in preventing increases in weight, BMI, and waist circumference only in a subgroup of patients being treated with olanzapine or clozapine but not other antipsychotics. Kang D et al³¹ reported that 1000 mg metformin/d was more efficacious than 36 mg betahistine/d in preventing and reversing the weight gain induced by antipsychotics. The inconsistent results may be attributed to the treatment duration, the treatment dose, and the type of antipsychotics. More potent histaminergic modulators may be required to elucidate the possible role of histaminergic pathways in human obesity.

In this study, the interaction effect of time and group was statistically significant on WHR after the 4-week double-blind betahistine/placebo treatment, but no obvious time main effects and no obvious group differences were detected. Smith et al³⁰ also did not find statistically significant changes in WHR before and after betahistine treatment, consistent with the final results of this study. This study also found that the interaction effect of time and group was statistically significant on LDL-C after the 4-week double-blind betahistine/placebo treatment, and the time main effect in the placebo group was significant. Therefore, we believe that the differences between the two groups of LDL-C after treatment are mainly due to the increased LDL-C levels in placebo group, rather than betahistine group. Antipsychotics with significant H₁ receptor affinity in the hypothalamus, particularly in the ventromedial nucleus, may cause weight gain in psychotic patients.³² Previous studies have shown that mice administered with clozapine and olanzapine, potent H₁ receptor antagonists, demonstrate greater activation of AMPK in hypothalamus,^33,34 which increases glucose levels and alters lipid metabolism.³⁵ Comparatively, antipsychotics are less likely to induce weight gain, eg ziprasidone, haloperidol, lurasidone and aripiprazole and have a minimal effect on AMPK activity and lipid metabolism.³³ The results of this study indicate that betahistine may delay the elevation of LDL-C in patients with chronic schizophrenia, which are consistent with the results of Kotańska et al.³⁴ To reveal the mechanisms underlay, Lian et al²⁶ found that olanzapine significantly enhanced the mRNA and protein expressions of H1R, the NPY mRNA expression, and AMPK-alpha activation; these changes were significantly reversed by co-treatment of olanzapine and betahistine compared with olanzapine only treatment.

Finally, this study also evaluated the impact of betahistine intervention on PANSS and TESS. The results showed that betahistine group showed no significant difference in psychiatric symptoms, compared with the placebo group, and no side effects related to betahistine occurred, which is consistent with previous studies.^25,28

Limitations

The small sample size and short intervention period are limitations of this study. Different antipsychotics used at baseline may have different effects on lipid metabolism. In the future, targeted studies involving larger populations with a longer follow-up period are required. Nevertheless, the dosage and duration of betahistine therapy is also an important factor affecting results. Further studies are needed to improve the research design.

Conclusions

Betahistine may potentially delay LDL-C increase in Chinese patients diagnosed with chronic schizophrenia. It does not affect the efficacy of the original antipsychotic, which provides new ideas for the treatment of metabolic syndrome in patients with chronic schizophrenia. Further research with a longer follow-up period designs is necessary to determine the safety and effectiveness of betahistine in antipsychotic-treated patients.