Buspirone: A forgotten friend

This older medication offers several advantages when treating anxiety or depression

n general, when a medication goes off patent, market- ing for it significantly slows down or comes to a halt. IStudies have shown that physicians’ prescribing hab- its are influenced by pharmaceutical representatives and companies.1 This phenomenon may have an unfore- seen adverse effect: once an effective and inexpensive medication “goes generic,” its use may fall out of favor. Additionally, physicians may have concerns about pre- scribing generic medications, such as perceiving them as less effective and conferring more adverse effects com- pared with brand-name formulations.2 One such generic medication is buspirone, which originally was branded as BuSpar. KIEFERPIX Anxiety disorders are the most common psychiatric Rachel Shmuts, DO diagnoses, and at times are the most challenging to treat.3 Assistant Professor Anecdotally, we often see benzodiazepines prescribed as Department of Psychiatry first-line monotherapy for acute and chronic anxiety, but Rowan University School of Osteopathic Medicine Stratford, New Jersey because these agents can cause physical dependence and a withdrawal reaction, alternative anxiolytic medications Abigail Kay, MD Associate Professor should be strongly considered. Despite its age, buspirone Department of Psychiatry and Human Behavior still plays a role in the treatment of anxiety, and its off-label Thomas Jefferson University Hospital use can also be useful in certain populations and scenar- Philadelphia, Pennsylvania ios. In this article, we delve into buspirone’s mechanism Melanie Beck, DO of action, discuss its advantages and challenges, and what PGY-1 Psychiatry Resident Cooper Medical School of Rowan University you need to know when prescribing it. AtlantiCare Regional Medical Center Camden, New Jersey

Disclosures Dr. Kay is a speaker for the American Association for the Treatment of Opiate Dependence and a suboxone trainer for the American Academy of Addiction Psychiatry. Drs. Shmuts and Beck report Current Psychiatry no financial relationships with any companies whose products are mentioned in this article, or 20 January 2020 with manufacturers of competing products. How buspirone works Advantages of buspirone Buspirone was originally described as Works well as an add-on to other medi- an anxiolytic agent that was pharmaco- cations. While buspirone in adequate logically unrelated to traditional anxiety- doses may be helpful as monotherapy in MDedge.com/psychiatry reducing medications (ie, benzodiazepines GAD, it can also be helpful in other, more and barbiturates).4 It has a high affinity complex psychiatric scenarios. Sumiyoshi for the 5-hydroxytryptamine 1A (5HT1A) et al10 observed improvement in scores receptor and may also act as a central on the Digit Symbol Substitution Test dopamine antagonist at D2 receptors.4,5 It when buspirone was added to a second- is FDA-approved only for the treatment generation antipsychotic (SGA), which of generalized anxiety disorder (GAD).4 suggests buspirone may help improve Buspirone also is commonly used as an attention in patients with schizophrenia. augmenting agent to selective serotonin It has been postulated that buspirone may reuptake inhibitors (SSRIs) in the treat- also be helpful for cognitive dysfunction ment of medication-resistant or partially in patients with Alzheimer’s disease.11 treated depression.6 When a patient who Buspirone has been used to treat comorbid is depressed appears to have marginal anxiety and alcohol use disorder, result- Clinical Point to no response to an adequate trial of a ing in reduced anxiety, longer latency to Buspirone is first-line agent, buspirone is thought to relapse, and fewer drinking days during replenish depleted stores and/or increase a 12-week treatment program.12 Buspirone commonly used synthesis of serotonin. Additionally, it has been more effective than placebo for as an augmenting acts directly on 5HT1A autoreceptors to treating post-stroke anxiety.13 agent to SSRIs achieve the desired desensitization of those Patients who receive an SSRI, such as in patients with receptors. All of these proposed mecha- citalopram, but are not able to achieve a treatment-resistant nisms are thought to improve symptoms substantial improvement in their depres- of depression.6 sive and/or anxious symptoms may ben- depression The antidepressants vortioxetine and efit from the addition of buspirone to their vilazodone exhibit dual-action at both sero- treatment regimen.14,15 tonin reuptake transporters and 5HT1A receptors; thus, they work like an SSRI A favorable adverse-effect profile. There and buspirone combined.6 Although some are no absolute contraindications to buspi- patients may find it more convenient to rone except a history of hypersensitivity.4 take a dual-action pill over 2 separate ones, Buspirone generally is well tolerated and some insurance companies do not cover carries a low risk of adverse effects. The these newer agents. Additionally, prescrib- most common adverse effects are dizziness ing buspirone separately allows for more and nausea.6 Buspirone is not sedating. precise dosing, which may lower the risk of adverse effects. Potentially safe for patients who are Buspirone is a major substrate for cyto- pregnant. Unlike many other first-line chrome P450 (CYP) 3A4 and a minor for agents for anxiety, such as SSRIs, buspi- CYP2D6, so caution must be advised if con- rone has an FDA Category B classifica- sidering buspirone for a patient receiving tion, meaning animal studies have shown any CYP3A4 inducers and/or inhibitors,7 no adverse events during pregnancy.4 The including grapefruit juice.8 FDA Pregnancy and Lactation Labeling Dose adjustments are not necessary for Rule applies only to medications that age and sex, which allows for highly con- entered the market on or after June 30, 2001; Discuss this article at sistent dosing.4 However, as with prescrib- unfortunately, buspirone is excluded from www.facebook.com/ MDedgePsychiatry ing medications in any geriatric population, this updated categorization.16 As with any lower starting doses and slower titration of medication being considered for pregnant buspirone may be necessary to avoid poten- or lactating women, the prescriber and tial adverse effects due to the alterations of patient must weigh the benefits vs the risks pharmacodynamic and pharmacokinetic to determine if buspirone is appropriate for Current Psychiatry processes that occur as patients age.9 any individual patient. Vol. 19, No. 1 21 continued Table and/or eating disorders.4 Additionally, the Prescribing buspirone: American Psychiatric Association prac- Clinical pearls tice guidelines for the treatment of major depressive disorder identify buspirone as a The maximum daily dose of buspirone is useful strategy in treating erectile dysfunc- 60 mg/d. Doses >60 mg/d do not appear to have been examined in the published literature tion and orgasmic dysfunction due to SSRI treatment.15 Be wary of drug–drug interactions with Buspirone for anxiety cytochrome P450 3A4 inducers and inhibitors, and depression because buspirone levels will be greatly Unlikely to cause extrapyramidal symp- affected by these medications toms (EPS). Because of its central D2 Buspirone is not recommended for patients antagonism, buspirone has a low poten- with hepatic and/or renal failure, but if it must tial (<1%) to produce EPS. Buspirone has be prescribed, do so with caution; lower doses will be necessary even been shown to reverse haloperidol- 21 The adverse-effects profile of buspirone is induced EPS. generally favorable, and no dose adjustments The Table4 highlights key points to bear are needed based on a patient’s age or sex in mind when prescribing buspirone. Clinical Point Food may decrease the bioavailability of buspirone, but it also decreases first-pass Unlike metabolism, so buspirone could be taken with Challenges with buspirone benzodiazepines, or without food as long as administration is consistent Response is not immediate. Unlike ben- buspirone does not Source: Reference 4 zodiazepines, buspirone does not have have an immediate an immediate onset of action.22 With onset of action buspirone monotherapy, response may be seen in approximately 2 to 4 weeks.23 No adverse events have been reported from Therefore, patients transitioning from a abrupt discontinuation of buspirone.17 quick-onset benzodiazepine to buspirone may not report a good response. However, Inexpensive. Buspirone is generic and as noted above, when using buspirone to extremely inexpensive. According to treat SSRI-induced sexual dysfunction, GoodRx.com, a 30-day supply of 5-mg response may emerge within 1 week.19 tablets for twice-daily dosing can cost $4.18 Buspirone also lacks the euphoric and A maximum daily dose (prescribed as 2 sedative qualities of benzodiazepines that pills, 15 mg twice daily) may cost approxi- patients may prefer. mately $18/month.18 Thus, buspirone is a good option for uninsured or under- Not for patients with hepatic and renal insured patients, for whom this would impairment. Because plasma levels of bus- be more affordable than other anxiolytic pirone are elevated in patients with hepatic medications. and renal impairment, this medication is not ideal for use in these populations.4 May offset certain adverse effects. Sexual dysfunction is a common adverse effect of Contraindicated in patients receiving SSRIs. One strategy to offset this phenom- MAOIs. Buspirone should not be pre- enon is to add bupropion. However, in a scribed to patients with depression who randomized controlled trial, Landén et al19 are receiving treatment with a monoamine found that sexual adverse effects induced oxidase inhibitor (MAOI) because the com- by SSRIs were greatly mitigated by add- bination may precipitate a hypertensive ing buspirone, even within the first week reaction.4 A minimum washout period of of treatment. This improvement was more 14 days from the MAOI is necessary before marked in women than in men, which initiating buspirone.9 is helpful because sexual dysfunction in women is generally resistant to other inter- Idiosyncratic adverse effects. As with all ventions.20 Unlike bupropion, buspirone is pharmaceuticals, buspirone may produce Current Psychiatry 22 January 2020 not contraindicated in patients with seizure idiosyncratic adverse effects. Faber and Sansone24 reported a case of a woman who Limited incentive for future research. experienced hair loss 3 months into treat- Because buspirone is available only as a ment with buspirone. After cessation, her generic formulation, there is little finan- alopecia resolved. cial incentive for pharmaceutical compa- MDedge.com/psychiatry nies and other interested parties to study Questionable efficacy for some anxiety what may be valuable uses for buspirone. subtypes. Buspirone has been studied as a For example, there is no data available on treatment of other common psychiatric con- comparative augmentation of buspirone ditions, such as social phobia and anxiety in and SGAs with antidepressants for depres- the setting of smoking cessation. However, sion and/or anxiety. There is also little it has not proven to be effective over pla- data available about buspirone prescribing cebo in treating these anxiety subtypes.25,26 trends or why buspirone may be under­ utilized in clinical practice today. Short half-life. Because of its relatively Unfortunately, historical and longitu- short half-life (2 to 3 hours), buspirone dinal data on the prescribing practices of requires dosing 2 to 3 times a day, which buspirone is limited because the original could increase the risk of noncompliance.4 branded medication, BuSpar, is no lon- Clinical Point However, some patients might prefer mul- ger on the market. However, this medica- Buspirone is a good tiple dosing throughout the day due to tion offers multiple advantages over other perceived better coverage of their anxiety agents used to treat anxiety, and it should option for patients symptoms. not be forgotten when formulating a who are uninsured or underinsured because it is extremely inexpensive schizophrenia: a randomized, double-blind, placebo- controlled study. Schizophr Res. 2007;95(1-3):158-168. Related Resources 11. Schechter LE, Dawson LA, Harder JA. The potential utility • Howland RH. Buspirone: Back to the future. J Psychosoc of 5-HT1A receptor antagonists in the treatment of cognitive Nurs Ment Health Serv. 2015;53(11):21-24. dysfunction associated with Alzheimer’s disease. Curr Pharm Des. 2002;8(2):139-145. • Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children 12. Kranzler HR, Burleson JA, Del Boca FK. Buspirone treatment and adolescents with anxiety: a review and Bayesian of anxious alcoholics: a placebo-controlled trial. Arch Gen analysis of abandoned randomized controlled trials. J Child Psychiatry. 1994;51(9):720-731. Adolesc Psychopharmacol. 2018;28(1):2-9. 13. Burton CA, Holmes J, Murray J, et al. Interventions for Drug Brand Names treating anxiety after stroke. Cochrane Database Syst Rev. Buspirone for anxiety 2011;12:1-25. Bupropion • Wellbutrin, Haloperidol • Haldol 14. Appelberg BG, Syvälahti EK, Koskinen TE, et al. Patients and depression Zyban Vilazodone • Viibryd with severe depression may benefit from buspirone Buspirone • BuSpar Vortioxetine • Trintellix augmentation of selective serotonin reuptake inhibitors: Citalopram • Celexa results from a placebo-controlled, randomized, double- blind, placebo wash-in study. J Clin Psychiatry. 2001; 62(6):448-452. 15. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. 3rd edition. https://psychiatryonline.org/pb/assets/ raw/sitewide/practice_guidelines/guidelines/mdd.pdf. treatment regimen for patients with anxiety Published May 2010. Accessed November 2019. and/or depression. 16. U.S. Food and Drug Administration. Pregnancy and lactation labeling (drugs) final rule. https://www.fda. Clinical Point gov/drugs/labeling/pregnancy-and-lactation-labeling- References drugs-final-rule. Published September 11, 2019. Accessed Buspirone is not 1. Fickweiler F, Fickweiler W, Urbach E. Interactions between November 26, 2019. physicians and the pharmaceutical industry generally and 17. Goa KL, Ward A. Buspirone. A preliminary review of its recommended for sales representatives specifically and their association with pharmacological properties and therapeutic efficacy as an physicians’ attitudes and prescribing habits: a systematic anxiolytic. Drugs. 1986;32(2):114-129. patients with hepatic review. BMJ Open. 2017;7(9):e016408. doi: 10.1136/bmjopen- 18. GoodRx. Buspar prices, coupons, & savings tips in U.S. area 2017-016408. code 08054. https://www.goodrx.com/buspar. Accessed or renal impairment 2. Haque M. Generic medicine and prescribing: a quick June 6, 2019. assessment. Adv Hum Biol. 2017;7(3):101-108. 19. Landén M, Eriksson E, Agren H, et al. Effect of buspirone 3. National Alliance on Mental Illness. Anxiety disorders. on sexual dysfunction in depressed patients treated https://www.nami.org/Learn-More/Mental-Health- with selective serotonin reuptake inhibitors. J Clin Conditions/Anxiety-Disorders. Published December 2017. Psychopharmacol. 1999;19(3):268-271. Accessed November 26, 2019. 20. Hensley PL, Nurnberg HG. SSRI sexual dysfunction: 4. Buspar [package insert]. Princeton, NJ: Bristol-Myers Squibb a female perspective. J Sex Marital Ther. 2002;28(suppl 1): Company; 2000. 143-153. 5. Hjorth S, Carlsson A. Buspirone: effects on central 21. Haleem DJ, Samad N, Haleem MA. Reversal of haloperidol- monoaminergic transmission-possible relevance to animal induced extrapyramidal symptoms by buspirone: a time- experimental and clinical findings. Eur J Pharmacol. related study. Behav Pharmacol. 2007;18(2):147-153. 1982:83;299-303. 22. Kaplan SS, Saddock BJ, Grebb JA. Synopsis of psychiatry. 6. Stahl SM. Stahl’s essential psychopharmacology: 11th ed. Philadelphia, PA: Wolters Kluwer; 2014. neuroscientific basis and practical applications, 4th ed. 23. National Alliance on Mental Health. Buspirone (BuSpar). Cambridge, United Kingdom: Cambridge University https://www.nami.org/Learn-More/Treatment/ Press; 2013. Mental-Health-Medications/Types-of-Medication/ 7. Buspirone tablets [package insert]. East Brunswick, NJ: Buspirone-(BuSpar). Published January 2019. Accessed Strides Pharma Inc; 2017. November 26, 2019. 8. Lilja JJ, Kivistö KT, Backman, JT, et al. Grapefruit juice 24. Faber J, Sansone RA. Buspirone: a possible cause of alopecia. substantially increases plasma concentrations of buspirone. Innov Clin Neurosci. 2013;10(1):13. Clin Pharmacol Ther. 1998;64:655-660. 25. Van Vliet IM, Den Boer JA, Westenberg HGM, et al. Clinical 9. Stahl SM. Stahl’s essential psychopharmacology: effects of buspirone in social phobia, a double-blind placebo prescriber’s guide, 6th ed. Cambridge, United Kingdom: controlled study. J Clin Psychiatry. 1997;58(4):164-168. Cambridge University Press; 2017. 26. Schneider NG, Olmstead RE, Steinberg C, et al. Efficacy 10. Sumiyoshi T, Park S, Jayathilake K. Effect of buspirone, of buspirone in smoking cessation: a placebo‐controlled a serotonin1A partial agonist, on cognitive function in trial. Clin Pharmacol Ther. 1996;60(5):568-575.

Bottom Line Buspirone is a safe, low-cost, effective treatment option for patients with anxiety and may be helpful as an augmenting agent for depression. Because of its efficacy and high degree of tolerability, it should be prioritized higher in our treatment Current Psychiatry 24 January 2020 algorithms and be a part of our routine pharmacologic armamentarium.