Buspirone has emerged as a significant anxiolytic medication, particularly favored for its gentler side effect profile compared to traditional anxiety treatments. Initially explored as an antipsychotic, buspirone demonstrated limited efficacy for psychosis but revealed notable anxiety-reducing properties. Approved by the United States Food and Drug Administration (FDA), buspirone is indicated for managing anxiety disorders and providing short-term relief from anxiety symptoms. Furthermore, it’s utilized off-label to augment unipolar depression therapies. Understanding How Buspirone Works is crucial for healthcare professionals. This article delves into the mechanism of action of buspirone, alongside its applications, adverse effects, and essential considerations for its use in patient care.
Indications for Buspirone Use
First synthesized in 1968 and patented in 1975, buspirone’s journey began with investigations into its antipsychotic potential. While it didn’t prove effective for psychosis, its anxiolytic properties led to its current therapeutic role. The resurgence in buspirone’s popularity is largely attributed to its reduced side effect burden compared to other anxiolytic drugs.
FDA-Approved Uses: Buspirone is officially approved for the management of anxiety disorders and the short-term alleviation of anxiety symptoms. Clinical trials have validated its effectiveness in outpatient settings, specifically for individuals diagnosed with generalized anxiety disorder (GAD). Buspirone is primarily employed in treating GAD, often considered as a second-line treatment option after selective serotonin reuptake inhibitors (SSRIs). It is considered when patients either don’t respond to SSRIs or experience intolerable side effects. Buspirone is also sometimes used to mitigate the sexual side effects associated with SSRIs. A key advantage of buspirone over benzodiazepines and barbiturates is its lack of potential for physical dependence and withdrawal, stemming from its negligible interaction with gamma-aminobutyric acid (GABA) receptors. However, it’s important to note that buspirone is not a fast-acting anxiolytic; its therapeutic effects typically manifest over 2 to 4 weeks. Despite this delayed onset, it has demonstrated comparable efficacy to benzodiazepines in managing GAD.
Off-Label Applications: Beyond its approved uses, buspirone is also employed off-label for augmenting unipolar depression treatment. The STAR*D trial provided evidence suggesting its effectiveness when used in conjunction with SSRIs for unipolar depression. Further research has explored its utility in reducing SSRI-induced sexual side effects and as a standalone treatment for depression. Emerging evidence indicates that buspirone, when combined with melatonin, may offer benefits in treating major depressive disorder and promoting neurogenesis.
It is critical to emphasize that buspirone is not indicated for managing withdrawal symptoms from benzodiazepines, barbiturates, or alcohol, again due to its lack of GABA receptor activity. Furthermore, studies suggest that buspirone’s effectiveness may be diminished in patients with a history of benzodiazepine treatment. Interestingly, research has explored other potential applications. A randomized controlled trial indicated that buspirone could improve central apnea, the apnoea-hypopnoea index, and oxygen saturation in heart failure patients. Another study identified buspirone as a possible treatment for gastroparesis and functional dyspepsia. However, more extensive clinical trials are needed to validate these off-label uses before buspirone can be widely recommended for these conditions in clinical practice.
Delving into the Mechanism: How Buspirone Works
Buspirone belongs to the azapirone class of drugs. Its primary mechanism of action revolves around its strong affinity for serotonin 5HT1a receptors, where it acts as a partial agonist. This partial agonism at 5HT1a receptors is believed to be the primary driver of its clinical anxiolytic effects. Buspirone also exhibits a weaker affinity for serotonin 5HT2 receptors and acts as a weak antagonist of dopamine D2 autoreceptors. Notably, it does not interact with benzodiazepine GABA receptors. How this partial 5HT1a agonism translates to anxiety relief is still being fully elucidated. One prevailing theory suggests that it enhances serotonergic activity in brain regions like the amygdala and other components of the brain’s fear and anxiety circuits. The delayed onset of buspirone’s anxiolytic effects suggests that its therapeutic action likely involves adaptive changes in 5HT1a receptors over time.
While primarily used for generalized anxiety disorder, buspirone’s potential extends to other neurological and psychiatric conditions. These include alleviating side effects of Parkinson’s disease treatment, ataxia, depression, social phobia, behavioral disturbances following brain injury, and symptoms associated with Alzheimer’s disease, dementia, and attention deficit disorders. However, further research is necessary to solidify buspirone’s effectiveness for these broader applications.
A molecular model of Buspirone, highlighting its chemical structure relevant to its pharmacological action.
Pharmacokinetics of Buspirone
Absorption: Buspirone is rapidly absorbed in the body but undergoes significant first-pass metabolism in the liver. Peak plasma concentrations are typically reached within 40 to 90 minutes after oral administration.
Distribution: Buspirone exhibits a high degree of plasma protein binding, with approximately 86% bound to plasma proteins.
Metabolism: The drug is primarily metabolized through oxidation by the cytochrome P450 enzyme CYP3A4. This metabolic process yields hydroxylated derivatives and a pharmacologically active metabolite known as 1-pyrimidinylpiperazine (1-PP).
Excretion: Buspirone has an elimination half-life of about 2 to 3 hours for the unchanged drug. Excretion mainly occurs through urine (29% to 63% as metabolites), with fecal excretion accounting for 18% to 38% of the administered dose.
Administration Guidelines
Buspirone is available in oral tablet form in various strengths: 5 mg, 7.5 mg, 10 mg, 15 mg, and 30 mg. For treating GAD in adults, the initial recommended dose is 15 mg daily, which can be administered as 7.5 mg twice daily or 5 mg three times daily. Dosage adjustments can be made every 2 to 3 days, increasing by 5 mg increments until the desired clinical response is achieved. The maximum recommended daily dose is 60 mg. Clinical trials have indicated that the typical therapeutic dosage range falls between 20 to 30 mg per day, administered in divided doses.
Buspirone has occasionally been used off-label for anxiety disorders in children. However, pediatric dosing is not firmly established. One pilot study in children aged 6 to 14 years initiated treatment at 5 mg daily, with weekly 5 mg increases, up to a maximum of 20 mg daily. A larger study involving patients aged 6 to 17 years explored a higher maximum daily dose of 60 mg. Food intake enhances buspirone’s bioavailability. Therefore, it is important to advise patients to take buspirone consistently with food or consistently on an empty stomach to maintain predictable drug levels. Buspirone’s metabolism via cytochrome P450 (CYP3A4) necessitates careful evaluation of potential drug-drug interactions before prescribing.
Specific Patient Populations:
- Hepatic Impairment: Patients with liver dysfunction exhibit significantly increased buspirone bioavailability (up to 13-fold). Dose reduction should be considered in these individuals.
- Renal Impairment: Renal impairment (creatinine clearance 10 to 70 mL/min/1.73 m) can increase buspirone bioavailability up to fourfold, warranting consideration for dose reduction.
- Pregnancy: Buspirone is classified as a Pregnancy Category B drug. The FDA’s Pregnancy and Lactation Labeling Rule has replaced the letter category system with narrative summaries of risks during pregnancy and lactation. Animal studies in rats have not revealed adverse effects on reproduction. The effects of buspirone during labor and delivery in humans are not well-defined.
- Breastfeeding: Limited data suggests that maternal buspirone doses up to 45 mg daily result in low levels in breast milk. Long-term effects of buspirone exposure through breast milk are unknown, and alternative medications may be preferred, especially when nursing newborns or preterm infants.
Adverse Effects Profile
Dizziness is a commonly reported side effect, affecting over 10% of patients.
According to FDA product labeling, adverse events reported in 1% to 10% of patients include:
- Central Nervous System: Abnormal dreams, ataxia, confusion, dizziness, drowsiness, excitement, headache, nervousness, numbness, outbursts of anger, paresthesia
- Ophthalmic: Blurred vision
- Otic: Tinnitus
- Cardiovascular: Chest pain
- Respiratory: Nasal congestion
- Dermatologic: Diaphoresis, skin rash
- Gastrointestinal: Diarrhea, nausea, sore throat
- Neuromuscular and Skeletal: Musculoskeletal pain, tremor, weakness
- Hepatic: Isolated cases of elevated serum enzymes without jaundice
These adverse reactions can often be mitigated by continuing therapy and gradually titrating the dose to an optimal therapeutic level. Notably, buspirone is associated with minimal sexual side effects and has even been shown to alleviate sexual side effects induced by SSRIs when used as an augmentation agent. Patients should be informed about the potential for central nervous system depression. Clinicians should also be aware of the rare possibility of akathisia (likely due to dopamine antagonism) and serotonin syndrome. Postmarketing surveillance has reported cases of somnambulism (sleepwalking) associated with buspirone, although underlying psychiatric conditions may also contribute. QT prolongation has been reported in patients with pre-existing cardiac conditions.
A visual representation of dizziness, a common side effect associated with buspirone use.
Contraindications for Buspirone
Buspirone is contraindicated in the following situations:
- History of hypersensitivity reaction to buspirone.
- Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days before or after MAOI therapy, due to the risk of serotonin syndrome and/or hypertensive reactions.
- Use in patients receiving reversible MAOIs such as linezolid or IV methylene blue, also due to the risk of serotonin syndrome.
Monitoring Buspirone Therapy
Regular follow-up appointments are essential after initiating buspirone treatment to monitor therapeutic efficacy and adverse effects. Patients should be encouraged to adhere to a consistent medication schedule and maintain consistency regarding taking it with or without food. As therapeutic effects typically take 2 to 4 weeks to manifest, patience is important. Many initial side effects may also subside over time. Healthcare providers should closely monitor for signs and symptoms of anaphylaxis, akathisia, and serotonin syndrome.
Given that buspirone is a CYP3A4 substrate, it is crucial to check for potential drug interactions that could alter its plasma concentration, including interactions with grapefruit juice, which can increase buspirone levels. Alcohol consumption can exacerbate CNS sedation, necessitating careful monitoring. Anxiety levels can be objectively assessed using tools like the GAD-7 (Generalized Anxiety Disorder-7) scale or the Hamilton Anxiety Scale (HAM-A) at baseline and during follow-up visits to gauge treatment response. The Institute for Safe Medication Practices (ISMP) highlights the potential for confusion between buspirone and bupropion, a dispensing error preventable through tall man lettering. Healthcare providers should verify accurate dispensing at each patient encounter.
Toxicity and Overdose
Buspirone exhibits low toxicity and a low potential for abuse compared to other anxiolytics. No fatalities have been reported from buspirone overdose alone. In pharmacological studies, healthy male subjects receiving up to 375 mg daily experienced symptoms like nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. While buspirone overdose typically results in full recovery, it is important to consider and investigate the possibility of co-ingestion of other medications. Literature reviews have documented reports of movement disorders, including dyskinesia, akathisia, myoclonus, parkinsonism, and dystonia, associated with buspirone.
In cases of buspirone-induced movement disorders, discontinuation of the drug is recommended. Treatment may involve centrally acting anticholinergic medications like trihexyphenidyl or benztropine, along with supportive care. Management of acute overdose involves symptomatic and supportive measures, including immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored, as in all drug overdose situations. Seizures are rare but may occur and can be treated with benzodiazepines. It’s important to note that there is no specific antidote for buspirone overdose.
Enhancing Healthcare Team Outcomes
Optimal use of buspirone necessitates a comprehensive understanding of its indications, dosing, adverse effects, and toxicity by the entire healthcare team. Clinicians are responsible for prescribing buspirone and counseling patients on the risk-benefit profile. Pharmacists play a crucial role in patient education regarding safe drug use and ensuring correct dosing, as well as communicating with physicians about any potential drug misuse. Nurses monitor for anxiety symptoms during follow-up visits and reinforce patient education. Residents and medical students should counsel patients against combining buspirone with other sedatives or alcohol. Patients requiring ongoing refills should be encouraged to seek psychiatric counseling.
Psychiatrists should conduct regular patient evaluations and share findings with the healthcare team. Emergency physicians and triage nurses are responsible for managing airway, breathing, and circulation in overdose situations. In cases of intentional overdose, the emergency department physician should notify the patient’s psychiatrist.
A collaborative, interprofessional team approach, involving clinicians, psychiatrists, nurses, pharmacists, and other healthcare providers, is crucial for optimizing buspirone therapy. This approach ensures optimal therapeutic outcomes, minimizes adverse effects, and ultimately improves patient outcomes in anxiety disorders. Evidence supports that interprofessional care and communication significantly enhance patient outcomes in anxiety disorders.
Review Questions
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References
(Note: References are present in the original article and are included below for completeness.)
1.Tiller JW. The new and newer antianxiety agents. Med J Aust. 1989 Dec 4-18;151(11-12):697-701. [PubMed: 2574409]
2.Garakani A, Murrough JW, Freire RC, Thom RP, Larkin K, Buono FD, Iosifescu DV. Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options. Front Psychiatry. 2020;11:595584. [PMC free article: PMC7786299] [PubMed: 33424664]
3.Howland RH. Buspirone: Back to the Future. J Psychosoc Nurs Ment Health Serv. 2015 Nov;53(11):21-4. [PubMed: 26535760]
4.Fava M, Targum SD, Nierenberg AA, Bleicher LS, Carter TA, Wedel PC, Hen R, Gage FH, Barlow C. An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. J Psychiatr Res. 2012 Dec;46(12):1553-63. [PubMed: 22998742]
5.Rafeyan R, Papakostas GI, Jackson WC, Trivedi MH. Inadequate Response to Treatment in Major Depressive Disorder: Augmentation and Adjunctive Strategies. J Clin Psychiatry. 2020 May 12;81(3) [PubMed: 32412697]
6.Chessick CA, Allen MH, Thase M, Batista Miralha da Cunha AB, Kapczinski FF, de Lima MS, dos Santos Souza JJ. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2006 Jul 19;2006(3):CD006115. [PMC free article: PMC8915394] [PubMed: 16856115]
7.Giannoni A, Borrelli C, Mirizzi G, Richerson GB, Emdin M, Passino C. Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial. Eur J Heart Fail. 2021 Feb;23(2):312-320. [PubMed: 32441857]
8.Tack J, Camilleri M. New developments in the treatment of gastroparesis and functional dyspepsia. Curr Opin Pharmacol. 2018 Dec;43:111-117. [PubMed: 30245474]
9.Loane C, Politis M. Buspirone: what is it all about? Brain Res. 2012 Jun 21;1461:111-8. [PubMed: 22608068]
10.Gammans RE, Mayol RF, LaBudde JA. Metabolism and disposition of buspirone. Am J Med. 1986 Mar 31;80(3B):41-51. [PubMed: 3515929]
11.Mahmood I, Sahajwalla C. Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet. 1999 Apr;36(4):277-87. [PubMed: 10320950]
12.Strawn JR, Mills JA, Cornwall GJ, Mossman SA, Varney ST, Keeshin BR, Croarkin PE. Buspirone in Children and Adolescents with Anxiety: A Review and Bayesian Analysis of Abandoned Randomized Controlled Trials. J Child Adolesc Psychopharmacol. 2018 Feb;28(1):2-9. [PMC free article: PMC5771537] [PubMed: 28846022]
13.Hohmann N, Haefeli WE, Mikus G. CYP3A activity: towards dose adaptation to the individual. Expert Opin Drug Metab Toxicol. 2016 May;12(5):479-97. [PubMed: 26950050]
14.Namazy J, Chambers C, Sahin L, Johnson T, Dinatale M, Lappin B, Schatz M. Clinicians’ Perspective of the New Pregnancy and Lactation Labeling Rule (PLLR): Results from an AAAAI/FDA Survey. J Allergy Clin Immunol Pract. 2020 Jun;8(6):1947-1952. [PubMed: 32084595]
15.Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Jul 15, 2024. Buspirone. [PubMed: 30000509]
16.O’Hanlon JF. Review of buspirone’s effects on human performance and related variables. Eur Neuropsychopharmacol. 1991 Dec;1(4):489-501. [PubMed: 1822316]
17.LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Sep 11, 2017. Buspirone. [PMC free article: PMC547852] [PubMed: 31643299]
18.Landén M, Eriksson E, Agren H, Fahlén T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1999 Jun;19(3):268-71. [PubMed: 10350034]
19.Rissardo JP, Caprara ALF. Buspirone-associated Movement Disorder: A Literature Review. Prague Med Rep. 2020;121(1):5-24. [PubMed: 32191616]
20.Moses TEH, Javanbakht A. New-Onset Sleepwalking in a Patient Treated With Buspirone. 2022 Jan-Feb 01J Clin Psychopharmacol. 42(1):96-98. [PMC free article: PMC8946643] [PubMed: 34928565]
21.Stock EM, Zeber JE, McNeal CJ, Banchs JE, Copeland LA. Psychotropic Pharmacotherapy Associated With QT Prolongation Among Veterans With Posttraumatic Stress Disorder. Ann Pharmacother. 2018 Sep;52(9):838-848. [PubMed: 29642718]
22.Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003 Sep;96(9):635-42. [PubMed: 12925718]
23.Morrison EK, Rowe AS. Probable drug-drug interaction leading to serotonin syndrome in a patient treated with concomitant buspirone and linezolid in the setting of therapeutic hypothermia. J Clin Pharm Ther. 2012 Oct;37(5):610-3. [PubMed: 22452676]
24.Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ. Grapefruit juice substantially increases plasma concentrations of buspirone. Clin Pharmacol Ther. 1998 Dec;64(6):655-60. [PubMed: 9871430]
25.Rush CR, Griffiths RR. Acute participant-rated and behavioral effects of alprazolam and buspirone, alone and in combination with ethanol, in normal volunteers. Exp Clin Psychopharmacol. 1997 Feb;5(1):28-38. [PubMed: 9234037]
26.Löwe B, Decker O, Müller S, Brähler E, Schellberg D, Herzog W, Herzberg PY. Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population. Med Care. 2008 Mar;46(3):266-74. [PubMed: 18388841]
27.Thompson E. Hamilton Rating Scale for Anxiety (HAM-A). Occup Med (Lond). 2015 Oct;65(7):601. [PubMed: 26370845]
28.Vaida AJ. The Institute for Safe Medication Practices and Poison Control Centers: Collaborating to Prevent Medication Errors and Unintentional Poisonings. J Med Toxicol. 2015 Jun;11(2):262-4. [PMC free article: PMC4469715] [PubMed: 25840933]
29.Salimi A, Razian M, Pourahmad J. Analysis of Toxicity Effects of Buspirone, Cetirizine and Olanzapine on Human Blood Lymphocytes: in Vitro Model. Curr Clin Pharmacol. 2018;13(2):120-127. [PubMed: 29766823]
30.Alam N, Najam R, Naeem S. Attenuation of methylphenidate-induced sensitization by co-administration of buspirone. Pak J Pharm Sci. 2016 Mar;29(2):585-90. [PubMed: 27087081]
31.Catalano G, Catalano MC, Hanley PF. Seizures associated with buspirone overdose: case report and literature review. Clin Neuropharmacol. 1998 Nov-Dec;21(6):347-50. [PubMed: 9844791]
32.Griffith JD, Jasinski DR, Casten GP, McKinney GR. Investigation of the abuse liability of buspirone in alcohol-dependent patients. Am J Med. 1986 Mar 31;80(3B):30-5. [PubMed: 3963032]
33.Strawn JR, Geracioti L, Rajdev N, Clemenza K, Levine A. Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review. Expert Opin Pharmacother. 2018 Jul;19(10):1057-1070. [PMC free article: PMC6340395] [PubMed: 30056792]
34.Muntingh AD, van der Feltz-Cornelis CM, van Marwijk HW, Spinhoven P, van Balkom AJ. Collaborative care for anxiety disorders in primary care: a systematic review and meta-analysis. BMC Fam Pract. 2016 Jun 02;17:62. [PMC free article: PMC4890271] [PubMed: 27250527]
