Buspirone

Buspirone may be the most understated anxiolytic in the pharmacopoeia. Its effects are so subtle, so deliberately modest, that many people taking it for the first time conclude it is not working at all. There is no onset in any dramatic sense -- no wave of calm, no melting of tension, no perceptible shift in consciousness. The compound operates on a timescale of weeks rather than minutes, its serotonergic modulation accumulating so gradually that the change is only visible in retrospect, like the movement of an hour hand.

Even after reaching steady state, the subjective experience of buspirone is defined more by absence than presence. The anxious chatter that normally fills the mind's idle moments grows quieter, but not silent -- it is as though the volume has been turned down by a few notches, not muted entirely. The physical symptoms of anxiety -- the tightness in the chest, the shallow breathing, the queasy stomach -- ease to a degree that is noticeable only when you pause to take inventory. There is no euphoria, no sedation, no cognitive impairment, no sense of being medicated. You simply feel slightly more like yourself on a good day.

In the first week or two of use, before the therapeutic effects have fully developed, the only subjective signs may be mild dizziness, a faint lightheadedness that passes quickly, and occasional nausea. These are not pleasant, but they are not particularly unpleasant either -- more like the minor physical oddities that accompany any new medication as the body adjusts. Some people report a brief, paradoxical increase in anxiety during this adjustment period, the nervous system's protest against an unfamiliar modulation of its serotonin signaling.

Once steady state is reached, the effects settle into a quiet background hum of anxiolysis. Social situations that previously provoked anticipatory dread become merely uncomfortable. Decision-making, previously paralyzed by anxious rumination, becomes incrementally easier. The catastrophizing that characterized anxious thought patterns loses some of its conviction, the worst-case scenarios it generates feeling less inevitable, less vivid, less real. None of these changes are dramatic. All of them are real.

The overall character of buspirone is one of gentle, invisible support. It does not impose a state; it clears a path. It does not sedate, intoxicate, or impair. It simply reduces the background noise of anxiety by enough to make a meaningful difference in daily functioning, doing so with such restraint that its presence is easier to detect by its absence -- when missed doses allow the old patterns of anxious thinking to reassert themselves, their return makes the medication's subtle work suddenly, retroactively visible.

Pharmacodynamics Buspirone acts primarily on the serotonin 5-HT1A receptor. It behaves as a full agonist at presynaptic 5-HT1A autoreceptors in the dorsal raphe, reducing the firing of serotonin-producing neurons, and as a partial agonist at postsynaptic 5-HT1A receptors in forebrain regions. This difference in activity between presynaptic and postsynaptic sites is thought to result from variations in receptor density and coupling efficiency.

Buspirone also has lower affinity for other serotonin receptors, including 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7, where it is thought to act primarily as an antagonist. In addition, buspirone has weak antagonistic activity at dopamine D2, D3, and D4 receptors, with preferential blockade of presynaptic D2 autoreceptors at low doses and postsynaptic D2 receptors only at higher doses.

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), circulates at higher levels than buspirone itself and is a potent α2-adrenergic receptor antagonist, which may contribute to some of buspirone's noradrenergic and dopaminergic effects. Buspirone has very weak affinity for α1-adrenergic receptors, and does not interact with the GABAA receptor complex, unlike benzodiazepines.

Buspirone has been found to produce antiaggressive effects in rodents.

Pharmacokinetics 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 1.5hours. It is reported to have an elimination half-life of 2.8hours, although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11hours, and one study even reported a terminal half-life of 33hours. 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=25nM) 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.

Buspirone was first synthesized by a team at Mead Johnson in 1968 but was not patented until 1980. It was initially developed as an antipsychotic acting on the D2 receptor but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic. In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. The patent expired in 2001, and buspirone is available as a generic drug.