Effect of Betahistine on Daytime Sedation and Metabolic Parameters in Patients with Schizophrenia on Second-generation Antipsychotics

Abstract

Background:

Second-generation antipsychotics (SGAs), widely used in the management of schizophrenia, have significant side effects like daytime sedation and metabolic derangement. Betahistine (H1 agonist) has shown promising results for metabolic parameters and is less studied for the management of daytime sedation.

Objectives:

This study aims to evaluate the effect of Betahistine on daytime sedation and metabolic parameters in patients with schizophrenia on SGAs from baseline to 6 weeks.

Methods:

This open-label randomized control trial will recruit 76 participants (Purposive sampling) aged >18 years, any gender, with a diagnosis of Schizophrenia on SGAs at AIIMS Bibinagar. Participants will be assessed for daytime sedation using the Epworth Sleepiness Scale (ESS) and for metabolic derangement using blood investigations and body measurements. Participants will be randomly allocated (via opaque, sealed envelopes) to two groups. Group 1 will receive Betahistine and treatment as usual, and Group 2 will receive treatment as usual (existing antipsychotics). Participants in both groups will be followed up at 2, 4, and 6 weeks.

Expected outcome:

Changes in daytime sedation will be assessed using ESS scores at each follow-up at 2, 4, and 6 weeks. Changes in metabolic parameters will be assessed using blood investigations and body measurements at baseline and 6 weeks.

Key Messages:

• Betahistine may reduce daytime sedation and improve metabolic derangements in patients with schizophrenia on SGAs.

• Combining Betahistine with treatment as usual may improve drug compliance and general well-being as a whole.

Despite the potential advantages of second-generation antipsychotics (SGA) over first-generation antipsychotics (FGA) with respect to reduced propensity to extrapyramidal symptoms in schizophrenia, they still pose certain treatment challenges. ¹ Medications like olanzapine, clozapine, quetiapine, and Ziprasidone are known to cause excessive daytime sedation, thereby preventing clinicians and patients from utilizing their benefits to the fullest. The relative risk for somnolence varies depending upon the choice and dose of antipsychotic (AP), along with the type of psychiatric disorder. ² A recent review, which included 36 placebo-controlled trials of APs in schizophrenia, found that among APs, olanzapine has the absolute risk increase (ARI) of 11.1% and the smallest NNH of 9, followed by Ziprasidone with an ARI of 8.6% and an NNH of 12. From the 16 head-to-head trials using different APs, the largest difference found was between clozapine versus olanzapine in a 24-month study (ARI 21.2%, NNH5). ³

The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, which compared multiple drugs simultaneously, found that the rates of hypersomnia and sleepiness were 31.0% for olanzapine, 30.7% for quetiapine, 28.4% for perphenazine, 28.2% for risperidone, and 24.3% for Ziprasidone. ⁴ Severe somnolence, especially in outpatient settings, can lead to accidents, loss of employment, failure at school, interpersonal problems, and/or neglect of self or others. The main clinical implications of this adverse effect are premature dose ceiling, compromised efficacy, and non-adherence in patients who show partial response. ³ Needless to mention, along with somnolence, the metabolic side effects (weight gain, dyslipidemia, diabetes) of SGA tend to influence the treatment course in most patients.^5,6 The common mechanism behind both these issues is the antihistaminic property (H1 receptor blockade) associated with these SGAs. ² Counteracting this effect with an agent that increases histamine will help nullify its effects on daytime sedation and weight gain.

Literature Review

Betahistine is an H1 receptor agonist and an H3 receptor antagonist, and is widely used to treat vertigo. Few RCTs evaluated the effect of adjunctive betahistine in the management of metabolic side effects and cognitive symptoms in patients receiving SGAs.^7,8 The results of these studies, though preliminary, are promising, as they found that adjunctive betahistine is useful in patients with these side effects.

Novelty

The efficacy of betahistine for daytime sedation has not been adequately studied. A recent case series found that adjunctive betahistine was useful in patients with clozapine-associated daytime sedation.^9,10 The efficacy of betahistine and olanzapine co-administration in mitigating somnolence was demonstrated in a recent RCT conducted among healthy women. ¹¹

With this background, we aimed to conduct an open-label parallel group randomized controlled trial using adjunctive betahistine in patients with schizophrenia and daytime sedation due to SGAs.

Objectives

In patients with schizophrenia receiving SGAs (Olanzapine, Risperidone, Clozapine, Quetiapine, and Ziprasidone).

Primary Objectives

1. To assess the change in daytime sedation from baseline → 2, 4, and 6 weeks between betahistine and treatment as usual (TAU) arms.

2. To assess the change in metabolic profile (Blood pressure, waist-hip ratio, Body mass index, fasting lipid profile, fasting blood sugar) from baseline → 2, 4, and 6 weeks between betahistine and TAU arms.

Secondary Objectives

1. To assess the Brief Psychiatric Rating Scale (BPRS) total scores between betahistine and TAU arms from baseline → 2, 4, and 6 weeks.

2. To assess the adverse events in both groups across different timelines (baseline → 2, 4, and 6 weeks) using the UKU side effects rating scale between betahistine and TAU arms.

3. To assess discontinuation and dropout rates across different timelines (baseline → 2, 4, and 6 weeks) between betahistine and TAU arms.

4. To assess the level of functioning between betahistine and TAU arms using the Global Assessment of Functioning (GAF) method across different timelines (baseline → 2, 4, and 6 weeks)

Methodology

Study Design/Study Participants/Setting

The study will be conducted in the Outpatient Department of Psychiatry for 2 years. The trial duration will be 6 weeks. Patients aged between 18 and 60 years of any gender with schizophrenia (as per ICD-11), on SGAs (Olanzapine, Risperidone, Clozapine, Quetiapine, and Ziprasidone) from the last 3 months ¹² will be recruited for the study. Participants with H/o asthma, peptic ulcer disease (diseases which a histamine analog may exacerbate), or history of pheochromocytoma or any other betahistine contraindication. Sedation due to any other reasons, like being on drugs- any other psychotropics like mood stabilizers, antidepressants, benzodiazepines, antihistaminics, muscle relaxants, opioids, etc., sleep disorders (OSA, narcolepsy, circadian rhythm disorders, etc.), head trauma, encephalitis, or brain tumors (assessed by history and verification of medical records), H/o aggression or suicidality, or any psychiatric emergency. Patients receiving prescriptions or over-the-counter medications taken for weight reduction. Patients on thyroid replacement therapy or lipid-lowering agents whose dosage changed by more than 50% in the past month. Pregnant or breastfeeding people will not be recruited for the study.

Sample Size

Sample size calculation was performed using G*Power 3. ¹³ Based on a previous study (Bai L et al., 2023), ¹⁴ an effect size of 0.9 (Cohen’s d) was computed from changes in Triglyceride levels at 4 weeks in both groups. However, with a moderate effect size of 0.7, a power of 80%, an alpha error probability of 0.05, and a 1:1 allocation ratio, the sample size per group was 34. However, with a dropout rate of 10%, the final sample size will be 76; 38 patients in the intervention group and 38 patients in the comparator group.

Tools and Instruments

Specifically designed sociodemographic and clinical proformas will be used. The diagnosis of schizophrenia will be confirmed based on ICD-11 criteria. The BPRS will be used to assess symptom severity, ¹⁵ and the GAF scale will be used to assess the severity of illness. ¹⁶ Epworth sleepiness scale (ESS), an 8-item questionnaire, will be used to assess the severity of daytime sedation. ¹⁷ Side effects and compliance will be assessed using the UKU side effect rating scale ¹⁸ and the Medication Adherence Rating Scale (MARS). ¹⁹ Metabolic parameters, including fasting blood sugar and lipid profile, will be assessed at baseline, 4 and 6 weeks.

Implementation Plan

The study will be conducted with the approval of the Institute Research Committee and the Institute Ethics Committee, and the trial is registered with the Clinical Trials Registry India (CTRI/2025/11/097271). All the individuals who fulfill the inclusion criteria will be approached for the study. The principal investigator will obtain informed consent from the study participants. Sociodemographic and clinical details will be recorded in an individual clinical proforma. Eligible patients will be randomized to either the intervention or the comparator group in a 1:1 ratio using computer-generated random numbers and fixed-block randomization (block size of 4). Allocation concealment will be achieved using sequentially numbered sealed/opaque envelopes. A separate person will be in charge of this, and the allocation of participants to either group will be revealed to investigators just before recruitment. Investigators or raters will not have access to these envelopes. Study participants in Group 1 will receive Betahistine and TAU, while study participants in Group 2 will receive only TAU.

Intervention

Participants in the intervention group will be started on betahistine 8 mg, with the dose increased every third day until reaching 16 mg TID. APs (TAU) will continue as such for 6 weeks. The dose of betahistine has been determined based on previous clinical trials for weight gain and case series on somnolence.^9,20

Treatment as Usual

The patients randomized to this group will continue existing APs.

Rescue and Concomitant Medication

Use of anticholinergics will be permitted during the trial; however, benzodiazepine use will not be allowed.

Assessment of Rating Scales

This will be done by an independent rater who is not a part of the study.

Timelines

Participants in both groups will be assessed at baseline, 2, 4, and 6 weeks. The follow-up assessments at 2 and 4 weeks will be conducted either in person or by telephone, and the in-person assessment at 6 weeks. At each follow-up, participants will be rated on the BPRS, GAF, ESS, UKU-SERS, and MARS. Metabolic parameters will be done at baseline and at 6 weeks (Figure 1 and SPIRIT 2025 participant timeline). At each follow-up, the investigator will perform a pill count to assess medication adherence. The timeline of the entire study duration is given in the GANTT chart (Table 1).

Figure 1.

ESS: Epworth Sleepiness Scale, BPRS: Brief Psychiatric Rating Scale, GAF: Global Assessment of Functioning, BMI: Body mass index, BP: Blood pressure, FBS: Fasting blood sugar, FLP: Fasting lipid profile, TAU: Treatment as usual, UKU-SERS: UKU side effect rating scale, MARS: Medication Adherence Rating Scale.

Table 1.

GANTT Chart Showing the Timeline of the Study Duration.

1. GANTT chart
Months →	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21	22	23	24
Tasks ↓
Recruitment of subjects and initial assessment
1st and 2nd assessments
3rd and 4th assessments
Data compilation and report writing

Ethics Review

Written informed consent to be obtained from the participants. Confidentiality about patient identity will be maintained. Participants will be informed of their right to withdraw from the study at any time. Participation/non-participation will not affect the treatment. No extra cost will be imposed on the patient; the investigators themselves will bear the additional cost of betahistine.

Data Collection and Statistical Analysis Plan

Data will be collected using case record proformas (CRPs) prepared for the study by the PI or Co-PI; each patient will be assigned a unique code at the time of recruitment. One investigator will be responsible for monitoring data intake, managing discrepancies, and performing electronic data entry. These validation checks will be done intermittently and randomly for patients’ CRPs. Scoring on scales will be performed by a designated investigator for all patients, with cross-checking by another investigator. After completing the intake, data from CRPs is entered into Microsoft Excel. Data will be verified for errors and cross-checked, then a clean dataset will be created. Only staff responsible for the study will have access to the data.

Statistical Analysis

Analysis will be conducted per the intent-to-treat protocol, and missing data will be handled using Maximum Likelihood Estimation. Statistical calculations will be performed using IBM SPSS Statistics version 20.0 (SPSS Inc, Chicago, Illinois, USA). For data analysis, we will use the Kolmogorov–Smirnov test to assess the normality of quantitative variables, analysis of variance (ANOVA) with repeated measures, Student’s t-test, the Bonferroni multiple pairwise comparison test, and the Chi-square test.

Measure of effect: Number needed to harm and Absolute risk reduction.

Discussion

Histamine is released from the tuberomammillary nucleus (TMN) of the posterior hypothalamus and projects to multiple hypothalamic nuclei (paraventricular nucleus, ventromedial hypothalamus, lateral hypothalamus, arcuate nucleus, dorsomedial hypothalamus) and to major brain areas (cortex, brainstem, hippocampus, striatum, nucleus accumbens, amygdala, and substantia nigra). It plays a major role in physiological processes such as sleep-wake states, food intake, body weight, appetite, drinking, locomotor activity, learning, and memory. ²¹ It exerts its action via histamine receptors H1–H4, which are G-protein-coupled receptors. Of these, H3 is an auto-receptor, located in the presynaptic region, which modulates the synthesis and release of histamine, and H1 receptors are present in the postsynaptic region of the hypothalamus, cerebral cortex, and limbic system, where they regulate the action of food intake, body weight, and sleep-wake state.^22,23

SGAs cause sedation, weight gain, and metabolic derangement by antagonizing H1 receptors, leading to histamine accumulation in the synaptic cleft and signaling H3 receptors to reduce histamine synthesis and release. ⁸

Betahistine, a histamine analog, has H3-antagonist and H1-agonist activity. Antagonism of the H3 receptor increases histamine synthesis and release. H1 agonism promotes wakefulness, reduces sedation, decreases food intake, and reduces weight gain.^22,23

Studies have also shown that betahistine also improves dyslipidemia associated with SGAs. ⁸

Expected Strengths

The study is a randomized controlled trial, which minimizes selection bias and enables comparability between the two groups. Assessments are made using standardized scales, and the study participants incur no extra cost.

Expected Limitations

The study is being conducted at a single center, limiting the generalizability of the findings. Being an open-label study, it can lead to observer bias.

Expected Outcomes

Participants receiving the intervention (Betahistine) are expected to have a reduction in daytime sedation compared to the control group. Further, participants receiving the intervention are expected to have improvement in metabolic parameters compared to the control group.

Supplemental Material

Supplemental material for this article is available online.

Supplemental Material

Supplemental material for this article is available online.

Supplemental Material

Supplemental material for this article is available online.

Supplemental Material

Supplemental material for this article is available online.