Buspirone

Medical uses

Buspirone is approved in the United States by the FDA for the short- or long-term treatment of anxiety disorders or can also be used for the short-term relief of the symptoms of anxiety. Likewise in Australia, buspirone is licensed for the treatment of anxiety disorders. In the United Kingdom, buspirone is indicated only for the short-term treatment of anxiety.

Although not approved for this indication, studies such as STAR*D have shown buspirone to be an effective augmentation agent alongside treatment with selective serotonin reuptake inhibitors (SSRIs) for clinical depression and is also used to counter the sexual side effects (anorgasmy and impotence) of the SSRI.

Several clinical trials, most randomised double-blind trials (and in one buspirone was used as an adjunct to atomoxetine) and one open-label, have been conducted to evaluate the utility of buspirone in the treatment of attention deficit hyperactivity disorder with mostly positive results.

Buspirone is also used in the treatment of mild to moderate cerebellar ataxia.

Dosage

For generalized anxiety disorder (GAD): 15–60 mg. Starting dose is 5 mg, 3 times daily, average dosage being 20–30 mg a day. If symptoms still persist after several weeks then the dose may be titrated up to 60 mg. Due to buspirone's short half-life and linear pharmacokinetics, dosage can be increased by 5 mg every two to three days.

Adverse effects

Adverse effects by incidence include:

Very common (>10% incidence)

Common (1–10% incidence)

Uncommon (0.1–1%)

Rare (<0.1% incidence)

Contraindications

Buspirone has these contraindications:

Interactions

Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:

The occurrence of elevated blood pressure has been reported when buspirone hydrochloride has been added to a regimen including a monoamine oxidase inhibitor (MAOI).

Overdose

Activated charcoal is believed to be an effective treatment for overdose, provided the patient is treated promptly.  Expected symptoms (based on symptoms in male healthy volunteers treated with 375 mg/day — compared to the maximum daily licensed dosage in Australia, the UK, and the US):

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available.

Pharmacology and mechanism

Buspirone functions as a serotonin 5-HT_1A receptor partial agonist (IA = 0.465).  It is this action that is thought to mediate its anxiolytic and antidepressant effects. Additionally, it functions as a presynaptic dopamine antagonist at the D₂, D₃ and D₄ receptors.   Buspirone is also a partial α₁ receptor agonist.  Buspirone also appears to produce some oxytocin stimulation via 5-HT1A receptor-induced action. Buspirone binds to 5-HT type 1A serotonin receptors on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus, thus reducing the firing rate of 5-HT-containing neurons in the dorsal raphe. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced.

Binding Profile of Buspirone (towards cloned human receptors)

Comparison to benzodiazepines

Buspirone's efficacy is comparable to that of members of the benzodiazepine family in treating GAD, although it tends to have a delayed onset of action.

Abrupt discontinuation of diazepam after six weeks of continuous administration resulted in withdrawal symptoms. This was not the case when administration of buspirone was ceased after six weeks. It may take several weeks before buspirone's anxiolytic effects become noticeable, and many patients may also need a higher dosage to adequately respond to treatment.

Buspirone's chemical structure and mechanism of action are completely unrelated to those of benzodiazepines and is not effective as a treatment for benzodiazepine withdrawal. Unlike benzodiazepines, buspirone is not a drug of abuse.

Synthesis

Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-Tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).

Analogues