Buspirone is an anxiolytic first synthesized in 1968 and patented in 1975. Initially, the drug was being developed as an antipsychotic but found not to be effective for psychosis, but it had anxiolytic features that were useful.  Buspirone has recently come back into favor.[1] This return to favor is mostly due to its decreased side-effect profile compared to other anxiolytic treatments. 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 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.[1] Buspirone is FDA approved for the short and long-term treatment of GAD, as well as short-term symptomatic relief of anxiety. It is 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.[2]

It is essential 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 diminish in patients who have had previous treatment with benzodiazepines.

Buspirone has a strong affinity for serotonin 5HT1a receptors, where it acts as a partial agonist, which is what some researchers believe produces the majority of clinical effects.[1] 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. How the partial 5HT1a agonism translates into clinical results remains largely unknown; however, some suspect it results 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.

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 reaching the desired clinical response. The maximum daily dosage is 60 mg per day. In clinical trials, a typical range of therapeutic effect 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.

Food intake decreases absorption; 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 understand that they must be consistent in whether they take food along with their medication.

Buspirone gets metabolized by cytochrome P450, CYP3A4, so any potential interactions should undergo an assessment 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, which occurs in over 10% of patients.

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

Many of these effects are relieved with the continuation of therapy and with a slow, gradual increase when finding 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.

Patients should receive a warning 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.

• Any history of hypersensitivity reaction with buspirone in the past
• Use of monoamine oxidase inhibitors (MAOI) within 14 days before or after buspirone therapy should be avoided due to the risk of developing serotonin syndrome and/or elevated blood pressure 
• Avoid starting buspirone in patients receiving reversible MAOIs such as linezolid or IV methylene blue due to risk of serotonin syndrome