A case report and literature review published in Medicine described a possible association between betahistine exposure and depressive symptoms with suicidal ideation in a 33-year-old male patient treated for dizziness of undetermined cause.
Betahistine is not approved by the FDA, although it remains widely used for vertigo and Ménière disease in many countries. The researchers noted that betahistine has been used in more than 80 countries, with estimated patient exposure exceeding 100 million.
The researchers said this was the first published individual case report they identified linking betahistine use with suicidality. However, they also noted prior database-level signals, including a safety-signal analysis that identified betahistine as a risk factor for suicide attempts and a World Health Organization VigiAccess search showing nearly 16,000 adverse-event reports involving betahistine, including 10 reports of suicidality or suicide attempts.
The patient initially presented with dizziness for 1 week. Cranial/cervical computed tomography, transcranial Doppler, electronystagmography, and balance testing showed no abnormalities, and the preliminary diagnosis was dizziness of undetermined etiology. The patient had no reported personal or family history of psychiatric disorders, no recent psychosocial stressors, no alcohol or substance use, and no concomitant medications known to induce depression or suicidality.
He was prescribed betahistine oral solution, 10 mL twice daily. His dizziness improved after 2 days of treatment, and he discontinued the medication. Five days later, dizziness recurred, and he restarted betahistine. After 2 days of rechallenge, his dizziness again improved, but he developed low mood, emotional detachment, and suicidal ideation. He also retrospectively reported milder similar symptoms during the first 2-day treatment course.
Betahistine was discontinued and replaced with difenidol hydrochloride tablets, a vestibular suppressant with a different mechanism involving muscarinic acetylcholine receptor antagonism rather than histamine receptor modulation. Suicidal ideation resolved completely within 2 days of betahistine withdrawal. During 3 months of follow-up, the patient reported no recurrence of suicidality, emotional detachment, or depressive symptoms.
The suspected adverse drug reaction was classified as “probable” using both the Naranjo Adverse Drug Reaction Probability Scale and the World Health Organization–Uppsala Monitoring Centre causality assessment system. The patient received a Naranjo score of 6, within the probable range of 5 to 8. The researchers cited the close temporal association, symptom resolution following withdrawal, recurrence after rechallenge, and lack of several identified alternative explanations as factors supporting the assessment.
The case was graded as grade 1, or mild, because the symptoms resolved after discontinuation and did not affect daily living. The researchers also noted that symptoms appeared milder during the first course and more severe after rechallenge, which they interpreted as consistent with reproducible patient-specific sensitivity.
The researchers proposed several possible mechanisms but emphasized that the pharmacologic basis remains uncertain. Betahistine acts as a weak H1 agonist and strong presynaptic H3 antagonist. They hypothesized that histamine receptor modulation could affect neurotransmitter systems involved in mood regulation, including serotonin, norepinephrine, gamma-aminobutyric acid, and histamine pathways. They also described possible pharmacogenomic vulnerability or subclinical mood-circuit instability as hypotheses, referring to unknown polymorphisms that could contribute to an idiosyncratic response.
The researchers acknowledged several limitations, including the single-case design, inability to establish definitive causality, potential recall bias, lack of generalizability, and inability to quantify risk or fully exclude confounding. Additional interpretive caveats include the patient’s undetermined dizziness diagnosis, the absence of a described structured psychiatric or suicidality assessment instrument, and the fact that resolution was confirmed by telephone follow-up.
The authors’ clinical lesson was not drug avoidance on the basis of this case alone, but vigilance for possible neuropsychiatric adverse reactions beyond psychotropic medications. They said newly emergent depressed mood, loss of interest, or suicidal ideation should be considered as potential adverse reactions to histamine receptor-active drugs when symptoms occur in close temporal proximity to treatment.
“This report aims to alert clinicians and pharmacists to break through the cognitive limitations of ‘only psychotropic drugs carry suicide risk,’” wrote study author Jiong Tang, MM, of the Department of Pharmacy at Chengdu Seventh People’s Hospital, Affiliated Cancer Hospital of Chengdu Medical College, and colleagues.
Disclosures: The study was supported by the Chengdu Medical Research Project. The researchers reported no conflicts of interest.
Source: Medicine