Hiccups are abrupt, involuntary contractions of the diaphragm and inspiratory musculature followed by sudden glottic closure, producing the characteristic sound^(1). Although transient hiccups are common and usually benign, persistent or intractable hiccups may cause substantial distress, sleep disturbance, impaired oral intake, fatigue, and reduced quality of life^(2). Persistent hiccups may additionally indicate underlying neurological, gastrointestinal, metabolic, infectious, or pharmacological etiologies^.(3)

Drug-induced hiccups are uncommon but increasingly recognized in clinical practice. Multiple pharmacological agents, including corticosteroids, anesthetics, chemotherapeutics, and psychotropic medications, have been implicated. Among psychotropics, antipsychotics—particularly aripiprazole—appear repeatedly in published literature, although antidepressants, benzodiazepines, stimulants, mood stabilizers, and sedative-hypnotics have also been reported.^(4-5)

The neurobiology of hiccups remains incompletely understood. Current evidence suggests involvement of a complex reflex arc incorporating central dopaminergic, serotonergic, and GABAergic pathways, vagal and phrenic nerve inputs, medullary centers, and respiratory musculature. Psychotropic medications may influence this circuitry through receptor-level effects, neurotransmitter modulation, or pharmacodynamic interactions.⁽⁶⁾

Despite growing recognition of psychotropics-associated hiccups, available evidence remains dispersed across isolated case reports and small case series. No large controlled studies or meta-analytic datasets currently exist. Therefore, synthesis of existing case-based evidence may help identify recurring clinical patterns, implicated drug classes, temporal associations, and therapeutic responses.

The present review aims to systematically synthesize published case-based literature on psychotropics-associated hiccups and provide clinically relevant insights regarding epidemiology, mechanistic hypotheses, and management considerations.

METHODOLOGY

Study Design

This review was conducted as a PRISMA-oriented qualitative systematic review with narrative synthesis focusing on published human case-based literature describing hiccups associated with psychotropic medications.

Literature Search Strategy

Literature searches were performed using PubMed and Google Scholar. Searches were conducted without date restrictions initially and ultimately covered case reports of hiccups induced by commonly used psychotropics between 1976 and 2024.

Following keywords and Boolean operators were used:

 ("hiccup*" OR hiccups OR hiccough OR singultus)
AND
(psychotropic* OR antipsychotic* OR antidepressant* OR benzodiazepine* OR stimulant* OR mood stabilizer* OR aripiprazole OR sertraline OR fluvoxamine OR clozapine OR perphenazine OR methylphenidate OR carbamazepine OR donepezil OR midazolam)

Manual bibliography screening was additionally performed to identify potentially relevant reports.

Eligibility Criteria

Inclusion Criteria

• Primary human case reports
• Case series
• Original case-based publications
• Reports explicitly describing hiccups temporally associated with psychotropic exposure

Exclusion Criteria

• Narrative reviews
• Editorials and commentaries
• Animal studies
• Duplicate case reports
• Purely mechanistic articles without clinical cases

Articles titled as “case report and review of literature” were included only when primary clinical data were presented.

Study Selection

Titles and abstracts were screened for relevance. Full-text evaluation was subsequently performed where available. Duplicate citations and overlapping reports were excluded. Approximately 300 records were initially screened, with 33 unique publications ultimately meeting eligibility criteria.

Quality Considerations

Given the predominance of isolated case reports and small case series, formal quantitative risk-of-bias analysis was not feasible. Instead, emphasis was placed on temporal plausibility, dechallenge/rechallenge relationships, consistency of reported patterns, and clinical coherence.

Reviewer Screening Procedure

Two authors participated independently in the screening and selection process. Initially, titles and abstracts retrieved by literature search were independently screened for relevance by one reviewer. Full texts or detailed abstracts of potentially eligible studies were subsequently assessed independently for inclusion. Any disagreements regarding study eligibility, inclusion, exclusion, or categorization were resolved through discussion and consensus with the second reviewer

Data Extraction

The following variables were extracted where available:

• Patient demographics
• Psychiatric diagnosis
• Implicated psychotropic agent
• Dosage and route
• Temporal relationship to treatment
• Clinical course
• Management strategies
• Outcomes
• Rechallenge/dechallenge observations

Due to inconsistent reporting across publications, some variables were unavailable in individual reports.

GENERATIVE AI was used to create the figures and helping prepare final draft of study.

Data Synthesis

A qualitative synthesis of the included studies which are case reports and case series were performed.

RESULTS

Study Characteristics

Thirty-three unique publications involving at least 35 identifiable clinical episodes were included. Publications spanned from 1976 to 2024. Most reports consisted of isolated case reports, while a minority represented small case series.

Antipsychotics represented the dominant implicated class. Aripiprazole alone accounted for 18 publications. Additional implicated agents included methylphenidate, sertraline, fluvoxamine, clozapine, risperidone, amisulpride, carbamazepine, donepezil, benzodiazepines, and hypnotics.

Several reports involved adolescents or pediatric populations.

Drug-Class Distribution

Antipsychotics accounted for the majority of reported cases, followed by benzodiazepines and antidepressants. Less commonly implicated categories included stimulants, mood stabilizers, hypnotics, and cognitive enhancers.

Principal Implicated Drug Classes

Table 1

Individual Agent Involvement

Aripiprazole emerged as the most frequently implicated individual medication. Other repeatedly identified agents included methylphenidate and sertraline.

Frequently Reported Agents

Table 2

Temporal Patterns

Hiccups commonly developed during:

• Treatment initiation
• Dose escalation
• Medication switching
• Combination therapy

Persistent or protracted hiccups were particularly associated with aripiprazole-containing regimens. Several cases described symptom emergence shortly after medication exposure, supporting a plausible temporal relationship.

Clinical Management and Outcomes

Management strategies varied substantially across reports. Interventions included:

• Drug discontinuation
• Dose reduction
• Medication switching
• Gabapentin
• Chlorpromazine
• Metoclopramide
• Flumazenil
• Add-on risperidone

Clinical improvement frequently followed withdrawal or reduction of the implicated medication.

Table 3.  Characteristics of Included Case Reports/Case Series on Psychotropics-Associated Hiccups

Table footnote:. Several reports lacked complete patient-level details regarding dose, route, exact latency, and follow-up; therefore, unavailable variables were recorded as “not fully detailed in current draft.”

DISCUSSION

This review synthesizes available case-based literature concerning psychotropics-associated hiccups across multiple psychotropic classes. Although evidence remains limited to case reports and small case series, several clinically meaningful patterns emerge.

The most striking observation is the predominance of aripiprazole-associated cases. Aripiprazole’s unique pharmacodynamic profile as a partial dopamine D2 receptor agonist with serotonergic activity may contribute to dysregulation within the hiccup reflex arc. Proposed mechanisms include alterations in dopaminergic modulation, serotonergic imbalance, and GABAergic signaling.

The hiccup reflex arc likely involves complex interactions between central neurotransmitter systems and peripheral neural pathways. Psychotropics may influence medullary respiratory centers, vagal and phrenic pathways, or brainstem interneuronal circuits. Individual susceptibility factors—including neurological vulnerability, concomitant medications, developmental stage, and psychiatric illness itself—may further modify risk.

Temporal patterns observed across reports strengthen the plausibility of psychotropics-associated hiccups as a genuine adverse drug reaction. Hiccups frequently emerged during treatment initiation, dose escalation, switching between antipsychotics, or exposure to combination regimens. Several reports also documented symptom resolution following drug discontinuation or dose reduction.

The predominance of antipsychotic-related cases may reflect both pharmacodynamic vulnerability and reporting bias. Antipsychotics are widely prescribed and often produce prominent neurophysiological effects capable of influencing respiratory and brainstem reflex pathways. Nevertheless, the repeated appearance of aripiprazole across multiple independent reports suggests a potentially meaningful signal warranting greater clinical attention.

Management approaches remain heterogeneous due to the absence of controlled studies. Drug discontinuation or dose reduction appeared most consistently beneficial. Gabapentin, chlorpromazine, metoclopramide, and flumazenil demonstrated benefit in selected cases. Clinicians should carefully evaluate temporal associations between medication exposure and symptom onset before initiating extensive diagnostic investigations.

Strengths and Limitations

This review provides a focused synthesis of psychotropics-associated hiccups across diverse psychotropic classes and highlights recurring clinical patterns within existing literature.

However, important limitations must be acknowledged:

• Evidence is limited predominantly to isolated case reports and small case series
• Publication bias is likely substantial
• Incidence and prevalence cannot be estimated
• Reporting quality varied considerably across studies
• Formal causality assessment was inconsistent
• Many reports lacked detailed dosing, management, or follow-up information

Consequently, conclusions should be interpreted cautiously.

CONCLUSION

Psychotropics-associated hiccups appear to represent an uncommon but clinically relevant adverse effect phenomenon. Antipsychotics—particularly aripiprazole—dominate the available case-based literature, although antidepressants, benzodiazepines, stimulants, mood stabilizers, and hypnotics have also been implicated.

Current evidence supports a probable role of dopaminergic, serotonergic, and GABAergic dysregulation within the hiccup reflex arc. Temporal associations with treatment initiation, dose escalation, switching, and combination therapy further support medication-related causality.

Clinicians should consider psychotropic exposure when evaluating persistent or unexplained hiccups in psychiatric populations. Greater pharmacovigilance and future prospective studies are needed to better define mechanisms, risk factors, and optimal management strategies.

REFERENCES

1. Steger M, Schneemann M, Fox M. Systemic review: the pathogenesis and pharmacological treatment of hiccups. Aliment Pharmacol Ther. 2015;42(9):1037-50.

1. Moretto EN, Wee B, Wiffen PJ, Murchison AG. Interventions for treating persistent and intractable hiccups in adults. Cochrane Database Syst Rev. 2013;(1):CD008768.
2. Chang FY, Lu CL. Hiccup: mystery, nature and treatment. J Neurogastroenterol Motil. 2012;18(2):123-30.
3. Friedman NL. Hiccups: a treatment review. Pharmacotherapy. 1996;16(6):986-95.

5. Kang JH, Hui D, Kim MJ, Kim HG, Kang MH, Lee GW, et al. Corticosteroid-induced hiccups: a systematic review. J Pain Symptom Manage. 2012;43(3):625-30

1. Petroianu GA. Hiccups and their treatment. J Clin Gastroenterol. 1997;25(3):461-6.

7. Miyaoka H, Kamijima K. Perphenazine-induced hiccups. Pharmacopsychiatry. 1999;32(2):81.
8. Ray P, Zia Ul Haq M, Nizamie SH. Aripiprazole-induced hiccups: a case report. Gen Hosp Psychiatry. 2009;31(4):382-4.
9. Zhang Y, Chen W, Chen J, Li M, Huang Y, Min W. Persistent hiccups due to aripiprazole: a case report and review of the literature. Front Pharmacol. 2024;14:1284510.
10. Carbone MG, Tagliarini C, Della Rocca F, Flamini W, Pagni G, Tripodi B, et al. Protracted hiccups induced by aripiprazole and regressed after administration of gabapentin. Case Rep Psychiatry. 2021;2021:5567152.
11. Kutuk MO, Berdzenishvili E, Aksu GG. Hiccups in an adult case with schizophrenia due to aripiprazole: a case report. Noro Psikiyatr Ars. 2021;58(1):77-8.
12. Kutuk MO, Tufan AE, Guler G, Yildirim V, Toros F. Persistent hiccups due to aripiprazole in an adolescent with obsessive-compulsive disorder responding to dose reduction and rechallenge. Oxf Med Case Reports. 2016;2016(4):66-7.
13. Serafini G, Piccinini G, Visimberga S, Cervetti A, Belvederi Murri M, Monacelli F, et al. Aripiprazole-induced persistent hiccup: a case report and review of the literature. Psychiatr Danub. 2019;31(1):26-31.
14. Sakalli Kani A, Ocek T, Aksoy-Poyraz C, Turan S, Duran A. Aripiprazole-induced acute hiccups: a case report. J Neuropsychiatry Clin Neurosci. 2015;27(1):e60.
15. Silverman MA, Leung JG, Schak KM. Aripiprazole-associated hiccups: a case and closer look at the association between hiccups and antipsychotics. J Pharm Pract. 2014;27(6):587-90.
16. Rao PN, Wu CL, YaDeau JT. Midazolam-induced hiccups reversed by flumazenil: a case report. A A Pract. 2021;15(11):e01547.
17. Li Z, Xiong Z, Jiang X, Li Z, Yuan Y, Li X. Hiccups induced by aripiprazole combined with sertraline in an adolescent with olfactory reference disorder: a case report. Front Psychiatry. 2022;13:793716.
18. Hori H, Nakamura J. Hiccups associated with switching from olanzapine to aripiprazole in a patient with paranoid schizophrenia. Clin Neuropharmacol. 2014;37(3):88-9.
19. Bilgiç A. Possible sertraline-induced hiccups in a boy with obsessive-compulsive disorder and attention-deficit/hyperactivity disorder. Clin Neuropharmacol. 2019;42(1):17-8.
20. Alamiri B, Naguy A. Methylphenidate-induced persistent hiccups in a child with ADHD relieved by add-on risperidone. Am J Ther. 2021;28(6):e706-e707.
21. Chang CC, Yang TC, Wang WF, Ju PC, Hsieh MH. Persistent hiccups related to long-acting aripiprazole injection: a case report. Psychiatry Clin Neurosci. 2022;76(12):678-80.
22. Micallef J, Tardieu S, Pradel V, Blin O. Benzodiazepine and hiccup: three case reports. Therapie. 2005;60(1):57-60.
23. Kutuk MO, Guler G, Tufan AE, Kutuk O. Hiccup due to aripiprazole plus methylphenidate treatment in an adolescent with attention-deficit/hyperactivity disorder and conduct disorder: a case report. Clin Psychopharmacol Neurosci. 2017;15(4):410-2.
24. Solla P, Congia S, Secchi L, Perra E, Cannas A. Clozapine-induced persistent hiccup in a patient with Alzheimer's disease. Clin Neurol Neurosurg. 2006;108(6):615-6.
25. Cheng CM, Tsai SJ. Persistent hiccups associated with switching from paliperidone to amisulpride. Psychiatry Clin Neurosci. 2015;69(6):383.
26. Yeh YW. Persistent hiccups associated with switching from risperidone to aripiprazole in a schizophrenic patient with cerebral palsy. Clin Neuropharmacol. 2011;34(4):135-6.
27. Cheng YM, Lin WA, Yang HN. Risperidone-induced hiccups in a youth with Down syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(2):641-2.
28. Bilgiç A, Yılmaz S, Yılmaz E. Hiccups associated with aripiprazole in an adolescent with bipolar disorder. J Child Adolesc Psychopharmacol. 2016;26(7):656-7.
29. Winstead DK. Hiccups following ingestion of oral chlordiazepoxide. Am J Psychiatry. 1976;133(6):719.
30. Mathews M, Mathews N, Menon N, Ahmad R, Papa-Molter A. Hiccups with dose titration of aripiprazole. Prim Care Companion CNS Disord. 2018;20(6):17l02251.
31. Benyakorn S. Aripiprazole-induced persistent hiccups: a case report. J Med Assoc Thai. 2017;100(8 Suppl):S212-S215.
32. Casanovas F, Oller Canet S, Pérez Oms A, García Hernández D, Llimona Sanchez C, Calls Samora M, et al. Hiccups, an uncommon side effect of antidepressants? A case report. Eur Psychiatry. 2020;63(Suppl 1):e1.
33. Ozen ME, Orum MH, Kalenderoglu A. Possible hiccup-inducing mechanism of aripiprazole: a case report. Adiyaman Univ Saglik Bilim Derg. 2018;58-62.
34. Akaltun I, Ayaydin H, Kara T. Hiccups in attention-deficit/hyperactivity disorder under methylphenidate treatment. Psychiatry Behav Sci. 2018;8(2):410.
35. Bozhüyük E, Poyraz CA, Poyraz BC, Özdemir A, Savrun BM, Arıkan MK. Persistent hiccups with fluvoxamine: a case report. Neuropsychiatr Invest. 2009;47(4):161-3.
36. Incecik F, Herguner OM. Carbamazepine-induced hiccups: a case report. J Pediatr Neurosci. 2022;17(2):181-2.
37. McGrane IR, Shuman MD, McDonald RW. Donepezil-related intractable hiccups: a case report. Pharmacotherapy. 2015;35(3):e1-e5.
38. Besenek M. Hiccups associated with switching from quetiapine to aripiprazole in an adolescent patient. Neurol Sci. 2020;33:214-7.
39. Vorona RD, Szklo-Coxe M, Ware JC. Hypnotic hiccups. BMJ Case Rep. 2014;2014:bcr2013202365..