Continuing Education Activity

Buspirone is an anxiolytic drug. Originally, the drug was being developed as an antipsychotic but was found ineffective for psychosis, but it had useful anxiolytic features. Buspirone has recently come into favor, mostly due to its decreased side-effect profile compared to other anxiolytic treatments. Buspirone is primarily used in the treatment of generalized anxiety disorder (GAD). This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of buspirone, pertinent for interprofessional team members for the treatment of patients where buspirone is indicated.

Objectives:

• Describe the mechanism of action of buspirone.
• Outline the indications for initiating buspirone.
• Summarize the contraindications associated with initiating buspirone.
• Review interprofessional team strategies for improving care coordination and communication to advance the use of buspirone and improve outcomes in disorders where indicated.

Indications

Buspirone is an anxiolytic first synthesized in 1968 and patented in 1975. Initially, the drug was being developed as an antipsychotic but was found ineffective for psychosis, but it had useful anxiolytic features. Buspirone has recently come back into favor. This return to favor is mostly due to its decreased side-effect profile compared to other anxiolytic treatments.[1]

FDA-approved Indication: Management of anxiety disorders or the short-term relief of the symptoms of anxiety. The efficacy of buspirone has been demonstrated in controlled clinical trials of outpatients whose diagnosis corresponds to generalized anxiety disorder(GAD). 

Off-label Clinical Use: Augmentation of unipolar depression. 

Buspirone's use is primarily for the treatment of generalized anxiety disorder(GAD). Typically, it is used as a second-line agent behind selective serotonin reuptake inhibitors(SSRIs) when a patient does not respond to or cannot tolerate the side effects of SSRIs. Buspirone has also been used as an augmentation agent to reduce SSRI's sexual side effects in particular. Unlike benzodiazepines and barbiturates, there is no associated risk of physical dependence or withdrawal with buspirone use due to the lack of effects on GABA receptors. However, buspirone has little efficacy as an acute anxiolytic as clinical effect typically takes 2 to 4 weeks to achieve. It is as effective as benzodiazepine treatment for GAD.[2]

The Sequenced Treatment Alternatives to Relieve Depression(STAR*D) trial showed evidence suggesting that buspirone could be effective as augmentation, alongside SSRIs, for unipolar depression. Further studies have also found some utility in subduing the sexual side effects of SSRIs and use as a single agent for the treatment of depression. Although the FDA does not approve these uses, evidence supports that buspirone combined with melatonin can treat the major depressive disorder(MDD) and promote neurogenesis.[3][4]

It is essential to recognize that buspirone has no use in treating withdrawal symptoms from benzodiazepines, barbiturates, or alcohol. Again, this relates to the lack of GABA receptor activity. Furthermore, the effects of buspirone have been shown to diminish in patients who have had previous treatment with benzodiazepines.[5]

Mechanism of Action

Buspirone is classified as azapirones. It has a strong affinity for serotonin 5HT1a receptors, where it acts as a partial agonist, which some researchers believe produces the preponderance of clinical effects. It also has a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors. There is no effect on benzodiazepine GABA receptors. The underlying mechanism behind how the partial 5HT1a agonism translates into clinical results remains largely unknown. It is proposed from increased serotonergic activity in the amygdala and other parts of the brain’s anxiety/fear circuitry. Due to the delayed anxiolytic effects seen clinically, buspirone likely provides relief through adaptations in 5HT1a receptors.[2]

Buspirone is primarily used to treat generalized anxiety disorder; however, it appears that buspirone may be useful in various other neurological and psychiatric disorders. Examples include attenuating side effects of Parkinson's disease therapy, ataxia, depression, social phobia, behavior disturbances following brain injury, and those accompanying Alzheimer's disease, dementia, and attention deficit disorders. Although additional effectiveness studies are warranted needed before using buspirone for the above-mentioned disorders.[6]

Administration

Buspirone is available in 5 mg, 7.5 mg, 10 mg, 15 mg, and 30 mg oral tablets. The initial recommended dose for GAD treatment is 15 mg per day, given as either 7.5 mg twice per day or 5 mg three times per day. Every 2 to 3 days, the dosage may be increased by 5 mg until the desired clinical response is reached. The maximum daily dosage is 60 mg per day. In clinical trials, a typical range of therapeutic effects was between 20 to 30 mg per day of divided doses.

Buspirone has seen occasional off-label use for pediatric anxiety disorders. The dosage has not been well established. In a pilot study of children aged 6 to 14 years, they were started on a daily dose of 5 mg and increased by 5 mg every week up to a maximum daily dose of 20 mg. Another more extensive study with patients aged 6 to 17 years had a higher maximum daily dose of 60 mg.[7]

Food intake decreases absorption; however, concomitant food intake also decreases the amount of the first-pass metabolism of the drug. Therefore, the net result of taking food with the medication is an increase in bioavailability. Because of this, clinicians should counsel the patients to take buspirone with food or take on an empty stomach. Consistency of dosage patterns is important.[8]

Buspirone gets metabolized by cytochrome P450, CYP3A4, hence evaluate potential interactions before an initial prescription. The measured bioavailability (using the steady-state area under the curve) increased fourteenfold in patients with hepatic impairment and twofold in patients with renal impairment.[9]

Adverse Effects

A common side effect is a dizziness, which occurs in over 10% of patients.[10]

According to FDA product labeling, the following reports of adverse events occurred in 1% to 10% of patients. 

• Central nervous system (CNS): 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 serum enzyme elevations without jaundice[11]

Clinicians can mitigate these adverse drug reactions by continuing therapy and gradual titration to an optimal therapeutic dose. Of note, buspirone has minimal sexual side effects. It has even been shown to help relieve the adverse sexual effects of SSRIs when given as an augmenting agent.[12]

Patients should receive a warning about the possibility of CNS depression. In addition, clinicians should inform patients of the rare potential for akathisia (likely due to central dopamine antagonism) and serotonin syndrome.[13]

Contraindications

• History of hypersensitivity reaction with buspirone in the past
• Avoid the use of monoamine oxidase inhibitors (MAOI) within 14 days before or after buspirone therapy. The aforementioned is due to the risk of developing serotonin syndrome and/or elevated blood pressure[14]
• Avoid buspirone in patients receiving reversible MAOIs such as linezolid or IV methylene blue due to the risk of serotonin syndrome.[15]

Monitoring

Offer frequent follow-up after initiating treatment to assess for therapeutic and adverse effects. Encourage patients to stay consistent with their medication schedule and whether they take it with food. As mentioned before, a therapeutic effect typically takes 2 to 4 weeks to take effect. Often, many of the adverse effects will lessen over time, as well. However, healthcare providers should closely monitor signs and symptoms of anaphylaxis, akathisia, and serotonin syndrome.[15]

Being a substrate of CYP3A4, buspirone should have continuous checking for interactions that can alter its plasma concentration; this includes grapefruit juice, which can increase its concentration. Alcohol use can worsen any CNS sedation, and its use requires strict monitoring as well.[16][17]

Assess anxiety levels by using the GAD-7 (general anxiety disorder-7) tool at baseline and follow-up visits to assess response to therapy. Similarly, clinicians can use the Hamilton anxiety scale(HAM-A)to objectify and rate a patient's anxiety severity.[18][19]

Toxicity

Relative to other anxiolytics, buspirone has low toxicity and potential for abuse. There have been no deaths reported from a buspirone overdose alone. In pharmacological trials, healthy male patients were given up to 375 mg per day and developed nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. While buspirone overdose typically resolves with complete recovery, high suspicion of other medication overdoses should be maintained and investigated.[20][21]

Buspirone is a Category B risk in pregnancy. On June 30, 2015, the US Food and Drug Administration (FDA) began implementation of the Pregnancy and Lactation Labeling Rule (PLLR), which replaced the pregnancy letter category system (A, B, C, D, and X) with integrated narrative summaries of the risks of using a drug or biological product during pregnancy and lactation[22]

Breastfeeding- Limited information indicates that maternal doses of buspirone up to 45 mg daily produce low levels in milk. Because no information is available on the long-term use of buspirone during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.[23]

In acute overdose, clinicians should use symptomatic and supportive measures along with immediate gastric lavage. Healthcare providers need to monitor respiration, pulse, and blood pressure as in all cases of drug overdosage. Seizures can occur in rare instances which require treatment with benzodiazepines. It is important to note that there is no specific antidote is known to buspirone.[24]

Enhancing Healthcare Team Outcomes

Before initiating buspirone therapy, it is essential to understand proper indications, dosing, adverse drug reactions, and toxicity. The clinician should prescribe buspirone for appropriate indication and counsel the patient on the risk vs. benefit ratio. The pharmacist must educate the patient on the safe use of the drug and ensure proper dosing. Additionally, the pharmacist must communicate with the physician if there is evidence of drug misuse in rare instances. In an era where drug abuse results in high mortality, the responsibility is on all healthcare workers to ensure that patients only use buspirone for legitimate purposes. The literature review suggests that buspirone has negligible abuse potential.[25]

Nurses should monitor for the signs and symptoms of anxiety during each follow-up visit. Nursing staff can also provide patient counseling to reinforce the pharmacists' advice. Residents and medical students should counsel the patient not to combine buspirone with other sedatives or alcohol. Patients who continue to get refills should be encouraged to seek counseling from a psychiatrist. Encourage individuals to be patient at the initiation of therapy and follow up within a month to assess the effectiveness of buspirone therapy.

The attending psychiatrist should evaluate the patient regularly and share their findings with the healthcare team. In overdose of buspirone, emergency physicians and triage nurses should establish patent airway, breathing, and circulation. Moreover, the emergency department physician should notify the psychiatrist if the overdose is deliberate.

Healthcare providers should use evidence-based medicine(EBM) and be well-informed about the latest guidelines regarding the current status of buspirone in treating generalized anxiety disorder.[26] As depicted above, clinicians(MDs, DOs, NPs, PAs), specialists, nurses, pharmacists, and other healthcare providers should closely collaborate with the patient on buspirone therapy. An interprofessional team approach can achieve optimal therapeutic results with minimal adverse effects leading to better patient outcomes. [Level 5]