Buspirone is an anxiolytic first synthesized in 1968 and patented in 1975. Originally the drug was being developed as an antipsychotic, but found to not be effective for psychosis, but it had anxiolytic features that were useful. Buspirone has recently come back into favor. This is 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). 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 SSRIs 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. Buspirone is FDA approved for the short and long-term treatment of GAD, as well as short-term symptomatic relief of anxiety. It has been shown to be as effective as benzodiazepine treatment for GAD.
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, as well as use as a single agent for the treatment of depression. Although the FDA does not approve these uses, some evidence has suggested the buspirone combined with melatonin has the potential to treat MDD and promote neurogenesis.
It is important to recognize that buspirone has no use in the treatment of the symptoms of withdrawal from benzodiazepines, barbiturates, or alcohol. Again, this relates to the lack of GABA receptor activity. Furthermore, the effects of buspirone have been shown to be diminished in patients who have been previously treated with benzodiazepines.
Buspirone has a high affinity for serotonin 5HT1a receptors where it acts as a partial agonist, which is believed to produce the majority of clinical effects. It also has weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors. There is no effect on benzodiazepine GABA receptors. How the partial 5HT1a agonism translates into clinical results remains largely unknown; however, it is suspected to be caused by 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.
Buspirone is offered 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 effect was found between 20 to 30 mg per day of divided doses.
Buspirone has been occasionally used off-label 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 larger study with patients aged 6 to 17 years had a higher maximum daily dose of 60 mg.
Absorption is decreased with food intake; however, concomitant food intake also decreases the amount of the first-pass metabolism of the drug. The net result of taking food with the medication is an increase in the bioavailability. Because of this, patients should be instructed to be consistent in whether they take food along with their medication.
Buspirone is metabolized by cytochrome CYP3A4, so any potential interactions should be assessed before an initial prescription. The measured bioavailability (using the steady-state area under the curve), increased 14-fold in patients with hepatic impairment and 4-fold in patients with renal impairment.
A common side effect is dizziness that occurs in over 10% of patients.
The following have been reported in 1% to 10% of patients:
Many of these effects are relieved with the continuation of therapy and with a slow, gradual increase when finding a 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.
Patients should be warned about the possibility of CNS depression. While rarer, patients should also be informed of the potential for akathisia (likely due to central dopamine antagonism) and serotonin syndrome.
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, the patient should be closely monitored for signs and symptoms of anaphylaxis, akathisia, and serotonin syndrome.
Being a substrate of CYP3A4, buspirone must be continuously checked for interactions that can alter its plasma concentration. This includes grapefruit juice, which can increase its concentration.
Alcohol use can worsen any CNS depression, and its use should be closely monitored as well.
Relative to other anxiolytics, buspirone has low toxicity and potential for abuse. No deaths have been 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 additional medication overdose should be maintained and investigated.
Buspirone is a Category B risk in pregnancy, and it is unknown whether it is present in breast milk. One case report states that buspirone was not transmitted via lactation, but the manufacturer does not recommend breastfeeding while taking the medication.
When considering the implementation of buspirone therapy, it is critical to recognize its strengths and weaknesses mentioned above. If a patient is an appropriate candidate, verify that they are invested in the treatment and have an understanding of the possible risks and benefits. Encourage individuals to be patient at the initiation of therapy and follow up within a month to assess effectiveness.