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CNS Drugs

, Volume 7, Issue 1, pp 68–88 | Cite as

Buspirone

An Updated Review of its Clinical Pharmacology and Therapeutic Applications
  • Bret Fulton
  • Rex N. Brogden
Adis Drug Evaluation

Abstract

Synopsis

Buspirone is an anxiolytic agent from the azapirone class of compounds. It differs structurally and pharmacologically from the benzodiazepines. Although the exact anxiolytic mechanism of action of buspirone is unknown, its primary pharmacological action is its binding to serotonin 5-HT1A receptors in the brain. Unlike benzodiazepines, buspirone has no demonstrated sedative effect and has little effect on psychomotor performance or cognition. In addition, animal and human studies have found little evidence that buspirone has abuse potential or dependence liability.

Recent large comparative trials have confirmed that buspirone is superior to placebo and has similar efficacy to benzodiazepines in the treatment of patients with anxiety. In comparative trials, patients receiving buspirone had reductions in Hamilton Anxiety Rating Scale (HAM-A) total scores ranging from 37 to 60%. By comparison, those receiving benzodiazepines had HAM-A total score reductions of 29 to 69%. Buspirone usually produced significant reductions in HAM-A total scores within 1 to 2 weeks of treatment initiation. Some studies have noted a faster onset of action with benzodiazepines than with buspirone, but larger, more recent trials have not confirmed this.

Buspirone has also demonstrated efficacy in patients with anxiety and coexisting alcohol (ethanol) abuse/dependence or depression. Buspirone not only reduces symptoms of anxiety in these patients but produces improvements in the comorbid disorder. In most studies, alcohol-dependent patients were significantly more likely to remain on treatment than those receiving placebo. In patients with mixed anxiety-depression, treatment with buspirone produced significant reductions in both the HAM-A and Hamilton Depression Rating Scale total scores. Buspirone produced significant improvements in the cardinal symptoms of depression (depressed mood, guilt, work and interest, anergia and diurnal variation of mood) which indicates that it may have an antidepressant effect independent of its anxiolytic activity.

In summary, recent clinical trials have verified the efficacy of buspirone in the treatment of anxiety disorders and confirmed its role as a well established alternative to benzodiazepines. Buspirone is particularly useful in patients wishing to avoid adverse effects associated with the benzodiazepines, such as sedation and performance and cognitive impairment, or those in whom abuse and dependence potential are a concern.

Pharmacodynamic Properties

Although the exact anxiolytic mechanism of action of buspirone is unknown, the drug is believed to act primarily through effects on central serotonergic systems. Buspirone binds both presynaptically and postsynaptically to serotonin 5-HT1A receptors in the brain. At presynaptic receptors in the dorsal raphé, buspirone acts as a full agonist; postsynaptically, it acts as a partial agonist at 5-HT1A receptors in the hippocampus. Buspirone also has a moderate affinity for presynaptic dopamine D2 receptors. Unlike benzodiazepines, it has no effect on the γ-amino-butyric acid (GABA)—benzodiazepine complex.

Buspirone has a low potential for producing sedation or impairment of psychomotor performance and cognition. When compared with various benzodiazepines, buspirone produces significantly less daytime sedation and has less effect on tests designed to measure psychomotor performance, including driving ability. Benzodiazepines significantly impaired memory function, but buspirone had no effect.

The abuse and dependence potential of buspirone appears to be minimal. In animal drug discrimination and drug self-administration studies, buspirone had no acute subjective intoxicating or reinforcing properties. In addition, benzodiazepines were significantly more likely to be preferred to buspirone in study participants with a history of substance abuse. The dependence liability of buspirone is lower than that of benzodiazepines as measured by significantly fewer withdrawal symptoms after drug discontinuation. Furthermore, buspirone is not cross-tolerant with benzodiazepines, as evidenced by the inability of buspirone to prevent benzodiazepine withdrawal symptoms after long term treatment with these drugs.

Pharmacokinetic Properties

Buspirone is well absorbed after oral administration; however, substantial first-pass metabolism reduces oral bioavailability to approximately 4%. At therapeutic dosages there is a linear relationship between dose and area under the plasma concentration-time curve (AUC). Administration of buspirone with food substantially increases the AUC.

Buspirone undergoes extensive metabolism to at least 7 major and 5 minor metabolites. Less than 1% of an administered dose is excreted unchanged in the urine. The elimination half-life of buspirone ranges from 2 to 11 hours.

The elimination of buspirone is reduced in patients with cirrhosis; however, interpatient variation is considerable. Some studies have also reported decreases in buspirone clearance in patients with renal impairment. The pharmacokinetic properties of buspirone do not appear to be changed in the elderly.

Therapeutic Efficacy

Data from several recent large comparative studies have confirmed that buspirone is superior to placebo and has equivalent efficacy to benzodiazepines in the treatment of patients with anxiety. After treatment periods of 3 to 6 weeks, buspirone 10 to 60 mg/day produced reductions in Hamilton Anxiety Rating Scale (HAM-A) total scores ranging from 37 to 60%. This compared with reductions in HAM-A total scores of 29 to 69% for patients receiving benzodiazepines. Buspirone also produced significant reductions in HAM-A total scores in a few trials in patients aged ≥ 65 years. HAM-A scores in patients receiving buspirone declined progressively over the treatment period and were usually significantly different from baseline or placebo within 1 to 2 weeks of treatment. Results of a few studies have shown that benzodiazepines have a faster onset of effect than buspirone, although this was not confirmed in recent, larger studies. Buspirone is effective in alleviating both the psychic and the somatic symptoms of anxiety; however, psychic symptoms generally declined first. Studies evaluating the long term efficacy of buspirone have confirmed that the drug is effective after treatment periods lasting up to 1 year.

Patients with anxiety and co-existing alcohol (ethanol) use disorders receiving buspirone were significantly more likely to remain on treatment than those receiving placebo in 3 of 4 studies. In these studies, buspirone also produced significantly greater reductions in anxiety and alcohol consumption than placebo.

The addition of buspirone to treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with major depression who had failed to respond, or had partially responded, to an adequate trial with an SSRI improved depressive symptoms. Preliminary studies suggest that buspirone may be useful in the treatment of agitation in patients with dementia.

In patients with mixed anxiety-depression, buspirone was significantly superior to placebo in reducing HAM-A total scores. It was also associated with significant reductions in Hamilton Depression Rating Scale (HAM-D) total scores. Significant reductions in the cardinal symptoms of depression (depressed mood, guilt, work and interest, anergia and diurnal variation of mood) in patients receiving buspirone indicated that the drug has intrinsic antidepressant properties.

Preliminary studies of the use of buspirone in other indications such as smoking cessation and of buspirone alone or combined with an SSRI in obsessive-compulsive disorder have been conducted. Results of these studies were inconclusive, and further research is needed to establish whether buspirone has a role in these conditions.

Tolerability

Buspirone is generally well tolerated. In pooled data from 17 clinical trials, the most commonly reported adverse events not seen at equivalent incidence in placebo recipients include dizziness, nausea, headache, nervousness, lightheadedness and dry mouth. However, the frequencies of drowsiness, insomnia and excitement were similar to those reported in patients receiving placebo. Neither age nor duration of treatment appears to affect the frequency of adverse events. There have been rare case reports of buspirone-induced psychological (psychosis, mania, panic attack) and neuromuscular (dystonia, dyskinesia) adverse events.

Data concerning the effects of buspirone overdose are limited; however, the drug appears to produce relatively mild symptoms. There are no reported deaths after overdose when buspirone was the sole ingestant.

Dosage and Administration

Buspirone should be initiated at a dosage of 15 mg/day, administered in 2 divided doses. The target therapeutic dosage is 30mg daily, which can be achieved by the second week of treatment. Maximum dosage is 45mg daily in the UK and 60 mg/day in the US. Dosage adjustments may be necessary in patients with severe hepatic or renal dysfunction, as there is some decreased elimination of buspirone in such patients (although interpatient variation is considerable). Dosage adjustments in the elderly do not appear to be necessary.

No pharmacokinetic or pharmacodynamic interactions have been found between buspirone and tricyclic antidepressants or benzodiazepines. Buspirone should not be coadministered with monoamine oxidase inhibitors because of reports of elevated blood pressure with combined use.

Keywords

Adis International Limited Anxiety Disorder Generalize Anxiety Disorder Panic Disorder Clin Psychiatry 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis International Limited 1997

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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