Buspirone, sold under the brand name Buspar, is an anxiolytic drug that is primarily used to treat generalized anxiety disorder (GAD). It is also commonly used to augment antidepressants in the treatment of major depressive disorder. Unlike most anxiolytics, the pharmacology of buspirone is not related to that of benzodiazepines, barbiturates, or carbamates (it is not a GABA receptor agonist), and so buspirone does not carry the risk of physical dependence and withdrawal symptoms for which those drug classes are known. Buspirone is not considered to be a drug-of-abuse, is safer in overdose than traditional anxiolytics, and is significantly less impairing at therapeutic doses.
|By mouth (oral)|
|Metabolism||Hepatic (via CYP3A4)|
|Metabolites||5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP|
|Biological half-life||2.5 hours|
|Chemical and physical data|
|Molar mass||385.50314 g/mol|
|3D model (JSmol)|
Buspirone is approved in the United States by the Food and Drug Administration (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.
Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2 to 4 weeks to manifest. The drug has been shown to be similarly effective in the treatment of GAD to benzodiazepines including diazepam, alprazolam, lorazepam, and clorazepate. Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD, although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).
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 dysfunction (anorgasmia and erectile dysfunction) associated with SSRIs. The drug has also been found to be effective in the treatment of depression as a standalone drug.
Several clinical trials, most randomized 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 (ADHD), with mostly positive results.
Buspirone may be useful in the management of irritability, agitation, and aggression in older patients with dementia and in pediatrics, although further research is necessary to more clearly establish its effectiveness.
Known side effects associated with buspirone include dizziness, headaches, nausea, nervousness, and paresthesia. Buspirone is relatively well-tolerated, and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects. In addition, buspirone does not produce euphoria, and is not a drug of abuse.
Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available. In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed. Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals. One death has been reported in association with 450 mg buspirone together with alprazolam, diltiazem, alcohol, cocaine.
Buspirone has been shown in vitro to be metabolized by the enzyme 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:
- Itraconazole: Increased plasma level of buspirone
- Rifampicin: Decreased plasma levels of buspirone
- Nefazodone: Increased plasma levels of buspirone
- Haloperidol: Increased plasma levels of haloperidol
- Carbamazepine: Decreased plasma levels of buspirone
- Grapefruit: Significantly increases the plasma levels of buspirone. See grapefruit–drug interactions.
|Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.|
Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity. It is a preferential full agonist of presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and a partial agonist of postsynaptic 5-HT1A receptors. In accordance, an animal study found that buspirone dose-dependently decreases serotonin levels in specific brain areas while increasing dopamine and norepinephrine levels. It is thought that the main effects of buspirone are mediated via its interaction with the 5-HT1A receptor. Some of its effects may be mediated via oxytocin release secondary to 5-HT1A receptor agonism.[non-primary source needed] Buspirone also has lower affinity for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors.
In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity. It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses. In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals. Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.
A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself, and is known to act as a potent α2-adrenergic receptor antagonist. It may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals. In addition, 1-PP may play an important role in the antidepressant effects of buspirone. Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor. However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner".
Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. It is reported to have an elimination half-life of 2.8 hours, although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours. Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans. The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo. As such, it is likely to play an important role in the therapeutic effects of buspirone. 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.
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).
Buspirone was first synthesized, by a team at Mead Johnson, in 1968, but was not patented until 1975.[additional citation(s) needed] It was initially developed as an antipsychotic drug acting on the D2 receptor, but was found to be ineffective in the treatment of psychosis and was repurposed as an anxiolytic. In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. The patent placed on buspirone expired in 2001 and it is now available as a generic drug.
Society and cultureEdit
Female sexual dysfunctionEdit
Buspirone/testosterone (tentative brand name Lybridos) is a combination formulation of buspirone and testosterone which is under development by a pharmaceutical company called Emotional Brain for the treatment of female sexual dysfunction.
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