section name header

Introduction

AHFS Class:

Generic Name(s):

Buspirone hydrochloride is an anxiolytic agent.2,4,70,89,112,131,132,133

Uses

[Section Outline]

Anxiety Disorders !!navigator!!

Buspirone is used for the management of anxiety disorders (anxiety and phobic neuroses)1,2,5,36,37,38,39,40,41,42,45,72,81,83,88,95,107,109,123,189,191 and for short-term relief of symptoms of anxiety.1,2,47,72,123 Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.1,2 The efficacy of buspirone for long-term use (i.e., longer than 3-4 weeks) as an anxiolytic has not been established by controlled studies,1,2,37,38,39,40,41,72,95,107,109 but the drug has been used in some patients for substantially longer periods (e.g., 6-12 months) without apparent loss of clinical effect.1,114,185,186,189,191 If the drug is used for extended periods, the need for continued therapy should be reassessed periodically.1,114

Generalized Anxiety Disorder

Efficacy of buspirone has been established principally in outpatient settings for the management of generalized anxiety disorder1,2,36,37,38,39,40,42,45,72,83,95,107,109,112,130,160 in which anxiety was present for periods of 1 month up to 1 year (average symptom duration: 6 months) of continual duration.1 Generalized anxiety disorder is characterized principally by unrealistic or excessive anxiety and worry (apprehensive expectation) about 2 or more life circumstances (e.g., worry about possible misfortune to a child who is in no danger, worry about personal finances for no good reason, anxiety and worry about academic, athletic, and/or social performance).121 The disorder is manifested as symptoms of motor tension (e.g., trembling, twitching, shakiness, muscle tension, restlessness), autonomic hyperactivity (e.g., sweating, palpitation and/or tachycardia, dyspnea, dry mouth, dizziness, clammy hands, hot flushes [ flashes]), and vigilance and scanning (e.g., hyperattentativeness, feeling keyed up or on edge, difficulty concentrating, insomnia, irritability).1,38,46,121 Although patients with generalized anxiety disorder may have another underlying mental disorder (axis I disorder), the focus of the anxiety and worry is unrelated to the latter disorder.1,38,121 In addition, symptoms of generalized anxiety disorder should not occur only during the course of a mood or psychotic disorder,1,38,121 nor should the anxiety be initiated and maintained by an underlying organic factor (e.g., hyperthyroidism, caffeine intoxication).121

Controlled studies in patients with generalized anxiety disorder have shown that buspirone at usual dosages is as effective as usual dosages of benzodiazepines (e.g., alprazolam,45,83 clorazepate,40,42,83,184 diazepam,36,37,38,39,40,41,72,81,83,88,107,109,130,160 lorazepam)45,83 and more effective than placebo37,38,39,40,41,72,81 in reducing symptoms associated with anxiety. Limited evidence suggests that buspirone may be more effective for cognitive and interpersonal problems, including anger and hostility, associated with anxiety,36,40,72,82,152,160,185,186 while benzodiazepines may be more effective for somatic symptoms of anxiety.72,82,152,160,185,186 The drug also has been shown to reduce symptoms of anxiety in patients with coexisting depressive symptoms.1 Buspirone therapy generally is associated with fewer and less severe adverse CNS effects (e.g., sedation, psychomotor impairment) compared with benzodiazepines36,37,39,40,41,42,43,45,49,50,51,63,70,82,88,93,112,113,114,115,116,117,118,119,120,121,122,123,130,152 and appears to have little, if any, dependence liability.1,2,6,52,55,63,75,77,84,87,92,93,98,112,123,124,184 Because of these differences, buspirone may be preferred as initial therapy in some patients with generalized anxiety disorder.36,45,50,51,52,55,73,74,112,185,186 The drug may be particularly useful in patients in whom potential adverse effects of benzodiazepines would be of concern (e.g., patients whose work or life-style requires mental acuity, geriatric patients who may be particularly sensitive to the adverse CNS effects of benzodiazepines)46,47,100,112,122,123,128,129,152,167 and/or those in whom the abuse potential, dependence liability, and/or potential withdrawal associated with benzodiazepines are of concern.52,55,84,89,92,123,128,129,152,153,154,156,167,184 In addition, buspirone may be safer than benzodiazepines in those patients with anxiety disorders who, despite all warnings, are considered likely to combine anxiolytic therapy with CNS depressants and/or alcohol.2,55,88,122,123 (See Drug Interactions: Alcohol and also Other CNS Depressants.)

Depressive Symptoms

In addition to symptoms of anxiety, buspirone has reduced depressive symptoms in patients with generalized anxiety disorder, as determined using the Hamilton (HAM-D) or Raskin depression rating scale.5,36,37,38,40,53,112,123 Buspirone generally has been as effective as benzodiazepines in relieving symptoms of depression in these patients,5,36,37,38,40,112 although the drug may be less effective than benzodiazepines in relieving sleep disturbances.5,36,38 It has been suggested that improvement in depressive symptoms observed in these patients actually may reflect improvement in anxiety symptoms that are included in the depression rating scales rather than an antidepressant effect per se,5 and additional study is needed to determine whether the drug has clinically important antidepressant activity.5,54 Buspirone also has been used in combination with antidepressants in a limited number of patients with symptoms of both anxiety and depression.59

Symptoms of Sexual Dysfunction

The efficacy of buspirone for the management of sexual dysfunction in patients with generalized anxiety disorder has not been established, but limited data suggest that the drug may improve sexual function in these patients.99 Although the improvement in sexual function paralleled improvement in anxiety in one study, other mechanisms may have been involved.99 Further study is needed to more fully elucidate the value of buspirone in these patients.99,185,186

Other Anxiety Disorders

Because buspirone may diminish anger and hostility6,40,72,82,154 and appears to be less likely than benzodiazepines to cause disinhibition,154 some clinicians suggest that buspirone may be preferred in patients with a history of aggression or in whom disinhibition has occurred during benzodiazepine therapy.154,185,186 Benzodiazepines may be preferred as initial therapy in patients with anxiety symptoms (e.g., insomnia, muscle tension) that might benefit from the sedative and/or muscle relaxant effects of these drugs.112,153,160,185,186 If buspirone is used in patients whose anxiety includes insomnia as a component, concomitant use of a sedative/hypnotic at bedtime may be necessary.48,93,112,186 Because buspirone may have a slower onset of action than some anxiolytics (e.g., diazepam) (see Dosage and Administration: Dosage),36,38,39,80,82,87,112,122,184 patients may become discouraged during initial therapy with the drug,112,122,123,184 particularly when buspirone is used for the short-term management of anxiety associated with severe stress.122,186

The influence of previous, long-term benzodiazepine therapy on the anxiolytic response to buspirone remains to be fully elucidated,44,71,86,109,124 but response may be discouraging in some patients,44,71,83,86,109,112,122,124,184 possibly because buspirone has a slower onset of action36,38,39,80,82,87,112,122,184 and does not attenuate manifestations of benzodiazepine withdrawal.60,71,86,109,122,124 In addition, the anxiolytic expectations of some patients who previously have received long-term benzodiazepine therapy may differ considerably from the actual effects of buspirone therapy, which also could contribute to a discouraging response to buspirone in such patients.44,109,112,184 Because of the sometimes discouraging response to buspirone in such patients, some clinicians suggest that newly diagnosed patients and those with no previous benzodiazepine use may be optimal candidates for buspirone therapy.109,124,184

Efficacy of buspirone in the management of panic attacks or disorder has not been established.5,56,88,89,123,128,157,168,169,186,192

Other Uses !!navigator!!

Results of an uncontrolled study suggest that relatively high dosages of buspirone hydrochloride (i.e., usually 40-60 but up to 90 mg daily) may provide some reduction in depressive symptoms in patients with major depression (nonmelancholic type), but not in patients whose major depression is of the melancholic type.54 Well-controlled studies, particularly those comparing buspirone with antidepressants, are necessary to determine whether buspirone has clinically important antidepressant activity.5,54

Although buspirone exhibited some evidence of neuroleptic potential in several animal models4,6,7,11,13,26,28,68,163,166,176 and reportedly has produced transient antipsychotic effects when administered in large doses to patients with schizophrenia,26 the drug has no established antipsychotic activity in humans at usual dosages1,2,4,6,11,13,26,106 and should not be used in place of appropriate antipsychotic therapy when such therapy is indicated.1,2

Because of buspirone's effects on dopamine receptors, the drug has been studied for potential therapeutic effects in patients with parkinsonian syndrome.57,58 At dosages of 10-70 mg daily, buspirone provided no clinically important improvement or deterioration in a limited number of patients with parkinsonian syndrome who were receiving antiparkinsonian therapy (e.g., levodopa/carbidopa, bromocriptine) concomitantly.57,58 At higher dosages, however, some deterioration in parkinsonian manifestations (e.g., functional disability) was observed.57,58 Therefore, current evidence indicates that buspirone is not useful in the management of parkinsonian syndrome and may exacerbate the syndrome at relatively high dosages.57,58 The drug may be useful, however, as an anxiolytic in parkinsonian patients, provided high dosages are avoided.58

Dosage and Administration

[Section Outline]

Administration !!navigator!!

Buspirone hydrochloride is administered orally.1,2 Concomitant administration of the drug with food can increase oral bioavailability of buspirone.1,2,30,34,88 Therefore, the manufacturer states that the drug should be given in a consistent manner relative to food intake.1 (See Drug Interactions: Food.)

The 15- and 30- mg tablets are provided as Dividose® tablets and are scored to be broken in 2 halves (each providing a dose of 7.5 and 15 mg, respectively, or in 3 thirds) (each providing a dose of 5 and 10 mg, respectively).1

Dosage !!navigator!!

For the management of anxiety disorders, the usual initial adult dosage of buspirone hydrochloride is 10-15 mg daily, usually in 2 or 3 divided doses.1,2,37,38,41,45,47,49,72,83,123,191,193 Dosage is increased as necessary in increments of 5 mg daily every 2-4 days, according to the patient's response and tolerance.1,2,5,37,38,41,72,83,123 In clinical studies, most patients responded to maintenance dosages of 15-30 mg daily in 2 or 3 divided doses.1,37,38,39,40,41,42,45,47,48,51,59,114,123,191 Modification of the usual adult dosage does not appear necessary for geriatric patients.34,47,112,113,114,193 The manufacturer recommends that adult dosage not exceed 60 mg daily.1,2,123

The manufacturer states that when buspirone is administered concomitantly with a potent CYP3A4 inhibitor, it should be administered at a low dosage (i.e., 2.5 mg once or twice daily) and that subsequent dosage adjustment of either drug should be based on clinical assessment.1 (See Drug Interactions: Drugs Affecting Microsomal Enzymes and see Dosage and Administration: Administration.)

Buspirone may have a slower onset of action than some anxiolytics (e.g., diazepam),36,38,39,80,82,87,112,122,184 and some patients may require motivation and education about the drug's effects during initial therapy to assure compliance.112,186 Symptomatic relief may occur during the first 2 weeks of buspirone therapy in some patients,38,123 but optimum anxiolytic effect usually requires at least 3-4 weeks of therapy;39,41,123,193 occasionally, 4-6 weeks may be required for optimum effect.87

The efficacy of continued buspirone therapy for longer than 3-4 weeks has not been established by controlled studies.1,2,37,39,40,41,123 However, the drug has been used for longer periods (e.g., several months to a year) without unusual adverse effect or decreased efficacy in some patients.1,82,87,92,114,123,184,189,191 If buspirone is administered for longer than 3-4 weeks, the need for continued therapy should be reassessed periodically.1,114 Dosage during prolonged maintenance therapy should be kept at the lowest effective level; once an adequate response has been achieved, dosage should be reduced gradually and subsequently adjusted according to the patient's response and tolerance.2,191

Discontinuance of benzodiazepines and some other anxiolytic agents has been associated with symptoms of withdrawal, and buspirone will not prevent the development of these symptoms.1,2,6,39,44,60,70,71,86,124 Therefore, it is important that therapy with such agents be withdrawn gradually in patients being switched to buspirone, particularly when therapy with one of these agents has been prolonged and/or when relatively high dosages were used.1,2,39,86

Dosage in Renal and Hepatic Impairment !!navigator!!

The need for modification of buspirone hydrochloride dosage in patients with renal impairment has not been fully elucidated, and the drug should be used with caution in such patients.34,104,112 There is some evidence that the pharmacokinetics of buspirone and its active metabolite, 1-pyrimidinylpiperazine (1-PP), are not affected substantially in patients with mild to moderate renal impairment.104 (See Pharmacokinetics: Elimination) In anuric patients, however, accumulation of 1-PP may occur, and adjustment in buspirone hydrochloride dosage may be necessary.104 Some clinicians suggest that dosage of the drug be reduced by 25-50% in anuric patients.104 However, other clinicians state that because of the high interindividual and intraindividual variability in plasma concentrations of buspirone and 1-PP, it is difficult to make dosage adjustment recommendations for patients with renal impairment. Based on results from other studies, several clinicians state that because of the high interindividual and intraindividual variability in plasma buspirone concentrations, dosing recommendations for patients with renal impairment receiving buspirone cannot be made at this time.204,205 In addition, the manufacturer states that the drug is not recommended for use in patients with severe renal impairment.1 The need for supplemental doses during hemodialysis has not been determined,104 but such doses do not appear necessary since the drug does not appear to be removed substantially by hemodialysis.34,104,186

Buspirone hydrochloride should be used with caution in patients with impaired hepatic function,34,110,112 and the need for reduced dosage should be considered.34,110,112 (See Pharmacokinetics: Elimination.) The manufacturer states that the drug is not recommended for use in patients with severe hepatic impairment.1

Cautions

[Section Outline]

Buspirone generally is well tolerated.1,2,5,37,39,41,42,59,61,62,63,83,89,95,112,113,114,122,191 A causal relationship between many adverse reactions and the drug has not been established but cannot be excluded.1 In controlled studies, the incidence of some adverse effects was similar in patients receiving buspirone or placebo.1

Nervous system effects (e.g., dizziness, headache, drowsiness, light-headedness) are the most common adverse effects of buspirone,1,2,5,36,37,38,42,45,58,61,62,89,114,123,130,191 but those secondary to CNS depression (e.g., sedation, psychomotor dysfunction) generally occur less frequently than with other currently available anxiolytics (e.g., benzodiazepines).1,2,5,36,37,38,39,42,45,50,61,62,63,70,76,82,88,89,112,122,128,129,130 In clinical studies, adverse reactions requiring discontinuance of buspirone therapy occurred in about 10% of patients and included nervous system effects (e.g., dizziness, insomnia, nervousness, drowsiness, light-headedness, headache, fatigue) and GI effects (e.g., nausea).1,2,36,191 There is some evidence that tolerance of buspirone's adverse effects (e.g., dizziness) may be slightly less in geriatric patients than in younger adults.47,112,193

The incidence and severity of adverse reactions to buspirone relative to dosage and duration of therapy have not been fully characterized;1,83 however, adverse effects appear to occur more frequently at increasing dosages54,58,83,185,186 but generally appear to diminish with time during continued therapy.114,191,193 Because buspirone can bind to central dopamine receptors,1,2,114 the possibility exists that chronic therapy could result in adverse effects secondary to changes in dopamine-mediated neurologic function.1,2,58,113,114 (See Cautions: Nervous System Effects.) Although clinical experience to date has failed to reveal substantial evidence of such long-term effects at usual dosages,1,2,122 the possibility of risk cannot be ruled out and additional experience is needed to determine buspirone's potential for long-term sequelae.1,2,58,113,128

Nervous System Effects !!navigator!!

The most frequent adverse effects associated with buspirone therapy are nervous system effects.1,2,36,37,38,42,45,58,61,62,89,112,114,123,130,191,193 In controlled studies, dizziness,1,2,5,37,42,45,50,53,59,61,62,63,76,79,83,95,112,114 drowsiness,1,2,5,41,42,45,61,79,112,113,114 and headache1,2,5,41,42,43,45,53,59,61,62,63,76,83,112,113,114 occurred in about 10% of patients;1,2,61,79,112 fatigue,1,2,5,42,61,112 nervousness,1,2,5,61,62,63,79,83,112,113 insomnia,1,2,53,58,61,112 and light-headedness1,2,37,45,53,58,61,76,95,112 occurred in about 5%;1,2,61,112 and excitement,1,2,61,62,63,112 depression,1,2,5,42,61,63,112 decreased concentration,1,2,61,112 nightmares/vivid dreams,61,83 anger/hostility,1,2,61,112,113 confusion,1,2,61 weakness,1,2,5,61,112 incoordination,1,2,61 paresthesia,1,2,61,83,112,113 numbness,1,2,61,83 and tremor1,2 occurred less frequently.1,2,5,61,112 In these studies, dizziness, headache, nervousness, light-headedness, paresthesia, and excitement occurred appreciably more frequently in patients receiving buspirone than in those receiving placebo.1,2,5,61,112 Insomnia and nervousness may become particularly evident at high dosages (e.g., 100 mg daily), and may be secondary to a dose-dependent stimulation of α-adrenergic (noradrenergic) cells of the locus ceruleus.58,123

Buspirone is relatively nonsedating compared with other currently available anxiolytics (e.g., benzodiazepines),1,2,5,36,38,39,41,42,45,55,61,79,82,112,122 although sedative effects (e.g., drowsiness, lethargy, sedation) may become more prominent as dosage is increased (e.g., at dosages exceeding 20 mg daily).5,15,49,50,73,74,96 In addition, buspirone's sedative effects often are most apparent during initiation of therapy or upward titration of dosage and tend to decrease with time.43,49,88,114,191 However, the drug's CNS effects show interindividual variation and the potential for their development may not be predictable in a given patient.1,2 Adverse effects resulting from CNS and psychomotor depression (e.g., drowsiness, fatigue, mental depression, confusion, decreased concentration, incoordination, weakness) generally occur less frequently with buspirone than with benzodiazepines (e.g., clorazepate, diazepam, lorazepam),1,2,5,36,37,38,39,42,45,50,61,62,63,70,76,82,88,89,112,122,128,129,130 while dizziness, headache, nervousness, and paresthesia generally occur more frequently with buspirone.42,45,61,62,63,83,112

Dream disturbances occur in at least 1% of patients receiving buspirone,1,2,61,83,191 but a causal relationship to the drug has not been established.1 Other adverse nervous system effects not directly attributed to the drug but occurring less frequently include depersonalization,1,2,49,52,83,84 dysphoria,1,2,49,52,83,84 noise intolerance,1,2 euphoria,1,2 fearfulness,1,2 loss of interest,1,2 dissociative reaction,1,2 hallucinations,1,2 suicidal ideation,1,2 and seizures.1,2 Claustrophobic feelings,1,2 cold intolerance,1,2 stupor,1,2 slurred speech,1,2 and psychosis1,2 occur rarely. Depression191 and increased appetite191 occasionally have emerged during chronic (i.e., 6 months or longer) therapy with the drug.

Buspirone's potential for causing acute and chronic changes in dopamine-mediated neurologic function (e.g., dystonia, parkinsonian-like manifestations, akathisia, tardive dyskinesia) has not been fully elucidated.1,2,57,58,113,195 Clinical experience to date suggests that the risk for such effects during buspirone therapy at usual anxiolytic dosages is minimal,1,2,57,58,122 and such experience has not revealed evidence of definitive extrapyramidal reactions directly attributable to the drug.2,123,185,191 However, akathisia,1,2,185,195 hypertonia,185 dystonia,195 tremor,185 involuntary movements,1,2 slowed reaction time,1,2 and rigid/stiff muscles1,2 reportedly have been associated with anxiolytic dosages of buspirone in a few patients. In addition, a syndrome of restlessness, appearing shortly after initiation of therapy with the drug, has been reported occasionally.1,2,83,195 This syndrome may have resulted from increased central α-adrenergic activity or from dopaminergic or other effects.1,2,57,58,195 In addition, extrapyramidal manifestations (e.g., akathisia, tremor, rigidity) also have occurred in at least one patient receiving a buspirone hydrochloride dosage substantially exceeding usual anxiolytic dosages.26 In a limited number of patients with parkinsonian syndrome, dosages of 10-70 mg daily caused no clinically important deterioration in manifestations of the syndrome, although some deterioration (e.g., in functional ability) was apparent at relatively high dosages (e.g., 90-100 mg daily).57,58 (See Uses: Other Uses.) Myoclonus, which may have been serotonergically mediated, also has been reported in at least one patient shortly after initiation of usual anxiolytic dosages of buspirone; the myoclonus resolved following discontinuance of the drug and administration of clonazepam.195

Increased anxiety, agitation, and restlessness accompanied by pressured speech and racing thoughts occurred in several patients with panic disorder or generalized anxiety disorder who were receiving buspirone with tricyclic antidepressants and/or alprazolam; these manifestations resolved within 1-5 days following discontinuance of buspirone therapy.169 Hypomania also has been reported in a patient with bipolar disorder and symptoms of anxiety concurrently receiving buspirone, lithium, tranylcypromine, and alprazolam; symptoms of hypomania resolved within 3 days following discontinuance of buspirone therapy in this patient.175 Although the mechanism is unclear, it has been suggested that these reactions may have been caused by a buspirone-induced increase in dopaminergic or α-adrenergic activity, effects of the drug on 5-HT1 receptors, and/or a possible drug interaction between buspirone and alprazolam.169,175

GI Effects !!navigator!!

Nausea42,45,61,62,63,76,83,113,114 has been reported in 6-8% of patients receiving buspirone in controlled studies,1,2,61,112 occurring more frequently than with placebo.1,2,61,63 Adverse GI effects occurring in 1-5% of patients include dry mouth,1,2,53,61,63,112,191 abdominal/gastric distress,1,2,61,63,83,191 diarrhea,1,2,61,63,83,112,113,191,193 constipation,1,2,45,61,63,191 and vomiting.1,2,47,61,62,63,79,191,193 Flatulence,1,2 anorexia,1,2 increased appetite,1,2,191 salivation,1,2 irritable colon,1,2 and rectal bleeding1,2 occur less frequently, and burning of the tongue occurs rarely,1,2 but these effects have not been directly attributed to the drug.1

Cardiovascular Effects !!navigator!!

Tachycardia and/or palpitation1,2,61,191 have been reported in about 1-2% of patients receiving buspirone, and nonspecific chest pain has been reported in at least 1% of patients;1,2,61,191 however, these effects have occurred at a frequency not appreciably different from that occurring with placebo.1,61,185,186 Syncope,1,2 hypotension,1,2 and hypertension1,2 occur less frequently, and cerebrovascular accident,1,2 congestive heart failure,1,2 myocardial infarction,1,2 cardiomyopathy,1,2 and bradycardia1,2 occur rarely; a causal relationship to the drug also has not been established for these effects.1

Dermatologic Effects !!navigator!!

Adverse dermatologic effects occur occasionally in patients receiving buspirone and include rash,1,2,61 edema,1,2 pruritus,1,2 flushing,1,2 easy bruisability,1,2 hair loss,1,2 dry skin,1,2 facial edema,1,2 and blisters.1,2 Acne and thinning of the nails occur rarely.1,2 A causal relationship to the drug for most of these dermatologic effects has not been established.1

Other Adverse Effects !!navigator!!

Buspirone produces a dose-dependent stimulation of prolactin secretion (see Pharmacology: Neuroendocrine Effects);27,28,49,88,111,112 however, the clinical importance of the drug's effect on prolactin has not been fully determined.88 Menstrual irregularities (e.g., spotting, amenorrhea),1,2 galactorrhea,1,2 and thyroid abnormalities1,2 have occurred occasionally in patients receiving buspirone, but a causal relationship has not been established.1 Increased or decreased libido,1,2,61 delayed ejaculation,1,2,71 and impotence1,2,61,71 also have occurred occasionally in patients receiving the drug,1,2 but therapy with the drug also has improved sexual function in some patients with generalized anxiety disorder and associated sexual dysfunction.99 (See Uses: Anxiety Disorders.)

Blurred vision1,2,61,113,191 has been reported in 2% of the patients receiving buspirone in controlled studies.1,2 A causal relationship for most other adverse effects generally has not been established, although such effects have been reasonably associated with buspirone therapy.1 Tinnitus,1,2,191 sore throat,1,2,191 and nasal congestion1,2 occur occasionally in patients receiving the drug. Redness and itching of the eyes,1,2 conjunctivitis,1,2 and altered taste1,2 or smell1,2 also occur occasionally. Rarely, inner-ear abnormality,1,2 eye pain,1,2 photophobia,1,2 and pressure on the eyes have occurred.1

Urinary frequency1,2,79 or hesitancy;1,2,61 dysuria;1,2 muscle aches/pain,191 cramps,1,2 spasm,1,2 and weakness;1,2 arthralgia;1,2 hyperventilation;1,2 dyspnea;1,2 and chest congestion1,2 occur occasionally in patients receiving buspirone. Fever,1,2 weight loss1,2 or gain,1,2,191 and increased serum aminotransferase (transaminase) concentrations (e.g., AST [SGOT], ALT [SGPT])1,2 also have been reported occasionally. Rarely, pelvic inflammatory disease,1,2 enuresis,1,2 nocturia,1,2 epistaxis,1,2 alcohol abuse,1,2 bleeding disturbance,1,2 loss of voice,1,2 and hiccups1,2 have occurred in patients receiving the drug. Eosinophilia,1,2 leukopenia,1,2 and thrombocytopenia1,2 also have occurred rarely.

Precautions and Contraindications !!navigator!!

Although buspirone generally is less sedating than other currently available anxiolytics and does not produce substantial impairment of cognitive or psychomotor function at usual dosages,1,2,51,61,62,70,80,83,84,85,86,87,88,89,90,100,112,122 the CNS effects of buspirone exhibit interindividual variation and may not be predictable.1,2 Therefore, patients should be cautioned that buspirone may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) and to avoid such activities until they experience how the drug affects them.1,2 While drug interaction studies indicate that buspirone does not increase substantially alcohol-induced impairment of motor and mental performance,1,2,6,15,50,51,63,73,74,78,79,112 patients should be advised that it would be prudent to avoid concomitant use.1,2 (See Drug Interactions: Alcohol.)

Buspirone does not exhibit cross-tolerance with benzodiazepines or other sedative/hypnotic drugs, and will not prevent symptoms of withdrawal that may occur following cessation of therapy with these drugs.1,2,6,39,44,60,70,71,86,124 Therefore, it is important that therapy with such drugs be withdrawn gradually in patients being switched to buspirone, particularly when therapy with one of these agents has been prolonged and/or when relatively high dosages were used.1,2,39,86 Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug being discontinued and its elimination characteristics.1,2,60,86 Clinicians should be aware that the development of any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal or muscle cramps, vomiting, sweating, flu-like symptoms without fever, or even seizures following initiation of buspirone therapy in patients previously receiving other anxiolytics and/or sedative/hypnotics may be manifestations of withdrawal from these drugs.1,2,60,87

Because the potential risk of buspirone-induced changes in dopamine-mediated neurologic function, particularly those associated with long-term therapy, currently has not been elucidated, the possibility that such changes could occur in patients receiving the drug should be considered.1,186 (See Cautions: Nervous System Effects.)

In patients currently receiving a monoamine oxidase inhibitor, buspirone therapy should not be initiated.1,2,63 (See Drug Interactions: Psychotherapeutic Agents.)

Buspirone should be used with caution in patients with impaired renal function, since the drug and its metabolites are excreted principally by the kidneys.1,2,34,64,110,112,116 Buspirone also should be used with caution in patients with hepatic dysfunction.1,2,34,110,112 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Buspirone has no established antipsychotic efficacy in humans at usual anxiolytic dosages, and the drug should not be used in place of appropriate antipsychotic therapy when such therapy is indicated.1,2

Buspirone is contraindicated in patients who are hypersensitive to the drug.1,2

Pediatric Precautions !!navigator!!

Safety and efficacy of buspirone in children younger than 18 years of age have not been established.1 Although safety and efficacy of buspirone in children have not been fully evaluated, the drug has been used in pediatric patients without unusual adverse effects.1 In 2 controlled studies in 559 pediatric patients 6-17 years of age with generalized anxiety disorder (GAD), no unexpected adverse effects were associated with buspirone; however, there was no difference in symptoms of GAD between those receiving buspirone 7.5-30 mg twice daily or placebo for 6 weeks.1 Long-term safety and efficacy of the drug in children younger than 18 years of age have not been evaluated.1

Geriatric Precautions !!navigator!!

Results of a study in about 600 geriatric patients (mean age: 70.8 years) indicate that safety and efficacy of buspirone in geriatric patients appear to be similar to those of younger adults (mean age: 43.3 years); no age-related differences in the pharmacokinetics of buspirone were observed. 1 Although postmarketing experience has not revealed differences in the incidence of adverse effects between geriatric patients and younger adults, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. 1

Mutagenicity and Carcinogenicity !!navigator!!

No evidence of buspirone-induced mutagenesis was seen in the Ames microbial mutagen test, with or without metabolic activation, or in the mouse lymphoma L5178Y/TK+ cell test system, nor was DNA damage observed in Wi-38 human cells.1 No chromosomal aberrations or abnormalities were observed in bone marrow cells of mice given one or five daily doses of buspirone.1

No evidence of carcinogenesis was observed after 24 months in rats receiving oral buspirone hydrochloride dosages up to 133 times the maximum recommended human dosage or after 18 months in mice receiving oral dosages up to 167 times the maximum recommended human dosage.1

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Reproduction studies in rats and rabbits using oral buspirone hydrochloride dosages up to 30 times the maximum recommended human dosage have not revealed evidence of fetal abnormality or impaired fertility.1 There are no adequate and controlled studies to date using buspirone in pregnant women, and the drug should be used during pregnancy only when clearly needed.1

The effect of buspirone on labor and delivery in women is not known, but no adverse effects were observed during reproduction studies in animals.1

Lactation

Although the extent of distribution of buspirone and its metabolites into human milk is not known, the drug and its metabolites are distributed into milk in rats.1 Therefore, the manufacturer recommends that the use of buspirone in nursing women be avoided whenever clinically possible.1

Drug Interactions

[Section Outline]

Psychotherapeutic Agents !!navigator!!

Elevations in blood pressure have been observed in several patients receiving buspirone and a monoamine oxidase (MAO) inhibitor concomitantly;1,2,63,196,197 however, no adverse sequelae were associated with these elevations. In addition, buspirone may have been partially responsible for a case of serotonin syndrome that resulted in death of a patient receiving buspirone, fluoxetine, and an MAO inhibitor (tranylcypromine) concomitantly.201,202 Pending additional data, it currently is recommended that buspirone not be used concomitantly with an MAO inhibitor1,2,63,196,197 and that at least 10 days elapse following discontinuation of an MAO inhibitor and administration of buspirone.196,197

In a patient with depression, generalized anxiety disorder, and panic attacks who was receiving concomitant buspirone and trazodone therapy, an increase in anxiety symptoms to a level comparable to that observed prior to buspirone therapy occurred when fluoxetine was added to the regimen.198 Although the mechanism of this possible interaction has not been established, it was suggested that fluoxetine may have either directly antagonized the therapeutic activity of buspirone or may have precipitated the anxiety symptoms through a separate mechanism.198 However, combined use of the drugs also has been reported to potentiate therapeutic efficacy in patients with obsessive compulsive disorder.199,200

Concomitant administration of buspirone and trazodone has resulted in a threefold to sixfold elevation in serum ALT (SGPT) concentrations in a few patients.1,2 However, in a study designed to attempt to confirm these findings, concomitant administration of the drugs was not associated with an interactive effect on aminotransferases.1,2 The manufacturer states that current evidence suggests that buspirone and trazodone can be used concomitantly, provided that liver function is monitored.2

Concomitant administration of buspirone and haloperidol has resulted in increased serum haloperidol concentrations.2,97 When oral buspirone hydrochloride 45 mg daily and oral haloperidol 5 mg daily were administered concomitantly in healthy adults, peak serum concentrations of haloperidol increased2,97,185 by about 30% and area under the serum concentration-time curve increased by 46%.185 Buspirone pharmacokinetics were not affected and the increase in haloperidol concentrations was not associated with a substantial increase in adverse haloperidol effects.2,97,185 It has been suggested that buspirone's effect on haloperidol concentrations may have resulted from competitive inhibition of oxidative dealkylation of haloperidol, since both drugs are metabolized principally via this pathway.2 The manufacturer states that the clinical importance of this interaction has not been established.1,2

Concomitant administration of buspirone hydrochloride 45 mg daily and amitriptyline hydrochloride 75 mg daily in healthy adults did not result in substantial changes in steady-state amitriptyline or nortriptyline (an active metabolite) concentrations.2,34,59 In addition, no increase in amitriptyline-induced adverse effects was observed during concomitant use of the drugs.2,34

Because the effects of concomitant use of buspirone and most other psychotherapeutic agents have not been studied to date, such use should be undertaken with caution.1

Protein-bound Drugs !!navigator!!

Because buspirone is highly protein bound, it theoretically could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs.1,2,34,94 The manufacturer states that therapeutic concentrations of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of buspirone binding to plasma proteins.1 Although an in vitro study indicated that buspirone did not displace some highly protein bound drugs (e.g., phenytoin, propranolol, warfarin),1,2,34,94 it may displace less firmly bound drugs (e.g., digoxin).1,2,94 In an in vitro protein binding study, aspirin increased free plasma buspirone concentrations by 23%, while flurazepam decreased free plasma buspirone concentrations by 20%, but the in vivo effects of aspirin or flurazepam on free buspirone plasma concentrations, and their clinical importance, are unknown.1,203 Also, there has been 1 report of increased prothrombin time when buspirone was added to the drug regimen of a patient receiving warfarin, phenytoin, phenobarbital, digoxin, and levothyroxine (Synthroid®).1 However, the manufacturer states that the clinical importance of these changes is unknown.1,203

Drugs and Food Affecting Hepatic Microsomal Enzymes !!navigator!!

In vitro, metabolism of buspirone has been shown to be mediated by the cytochrome P-450 (CYP) isoenzyme 3A4. Drugs (e.g., erythromycin, itraconazole, nefazodone) that inhibit this enzyme increase plasma concentrations of buspirone, and drugs (e.g., rifampin) that induce this enzyme decrease plasma concentrations of buspirone. 1,204,206 Therefore, if buspirone is to be administered concomitantly with a drug that is a potent inhibitor of the CYP3A4 isoenzyme, a low buspirone dosage (e.g., 2.5 mg once or twice daily) is recommended, and subsequent dosage adjustment of either drug should be based on clinical assessment.1 Alternatively, when buspirone is used concomitantly with a drug that is a potent inducer of the CYP3A4 isoenzyme, dosage adjustment of buspirone may be necessary to maintain the anxiolytic effect.1

Erythromycin

In a study in healthy individuals, concomitant use of buspirone (10 mg daily) and erythromycin (1.5 g daily) increased peak plasma buspirone concentrations and area under the plasma concentration-time curve (AUC) by fivefold and sixfold, respectively,1,204 and was accompanied by an increased incidence of adverse effects attributable to buspirone.1 Therefore, the manufacturer states that if buspirone is administered concomitantly with erythromycin, a low buspirone dosage (e.g., 2.5 mg twice daily) is recommended, and subsequent dosage adjustment of either drug should be based on clinical assessment.1

Itraconazole

In a study in healthy individuals, concomitant administration of buspirone (10 mg daily) and itraconazole (200 mg daily) increased peak plasma buspirone concentrations and AUC 13- and 19-fold, respectively,1,204 and was accompanied by an increased incidence of adverse effects attributable to buspirone.1 Therefore, if buspirone is administered concomitantly with itraconazole, a low buspirone dosage (e.g., 2.5 mg once daily) is recommended by the manufacturer, and subsequent dosage adjustment of either drug should be based on clinical assessment.1

Nefazodone

In a steady-state pharmacokinetics study in healthy individuals, concomitant administration of buspirone (2.5 or 5 mg twice daily) and nefazodone (250 mg twice daily) increased peak plasma buspirone concentrations and AUC 20- and 50-fold, respectively, and substantially decreased buspirone metabolite 1-pyrimidinylpiperazine (1-PP) plasma concentrations by about 50%.1 Also, AUCs of nefazodone, hydroxynefazodone, and meta-chlorophenylpiperazine were increased by 23, 17, and 9%, respectively, and peak plasma concentrations of nefazodone and hydroxynefazodone were increased by 8 and 11%, in individuals receiving buspirone 5 mg twice daily with nefazodone.1 In addition, lightheadedness, asthenia, dizziness, and somnolence have been reported in patients receiving buspirone (5 mg twice daily) and nefazodone (250 mg twice daily); these adverse effects also have been reported when either drug was administered alone.1 Therefore, if buspirone is used concomitantly with nefazodone, a low buspirone dosage (e.g., 2.5 mg once daily) is recommended by the manufacturer, and subsequent dosage adjustment of either drug should be based on clinical assessment.1

Calcium-Channel Blocking Agents

In a small study in healthy individuals, concomitant administration of buspirone (10 mg as a single dose) with verapamil (80 mg 3 times daily) or diltiazem (60 mg 3 times daily) increased peak plasma concentrations of buspirone by 3.4 or 4-fold, respectively, and increased AUC of buspirone by 3.4- or 5.5-fold, respectively. 1,204 Because of the increased potential for adverse effects during concomitant use of buspirone with verapamil or diltiazem,1,204 the manufacturer suggests that dosage adjustment may be necessary. 1

Rifampin

Administration of a single 30-mg dose of buspirone to healthy individuals receiving rifampin (600 mg daily for 5 days) decreased peak plasma concentrations and AUC of buspirone by 83.7 and 89.6%, respectively. 1,204,206 Decreased pharmacodynamic effects also were reported.204,206 The manufacturer of buspirone recommends that if the drug used concomitantly with rifampin, dosage adjustment of buspirone may be necessary to maintain anxiolytic effect.1

Grapefruit Juice

In healthy individuals, concomitant administration of buspirone (10 mg as a single dose) with double-strength grapefruit juice (200 mL administered 3 times daily for 2 days) increased the peak plasma concentration and AUC of the drug by 4.3- and 9.2-fold, respectively.1,204 Therefore, the manufacturer states that concomitant administration of buspirone with large quantities of grapefruit juice should be avoided.1

Cimetidine !!navigator!!

Current limited evidence suggests that concomitant use of usual dosages of buspirone and cimetidine would be unlikely to result in a clinically important interaction.119,120,194 In a study in healthy adults, there was some evidence of cimetidine-induced changes in buspirone pharmacokinetics (e.g., shortened elimination half-life of buspirone, increased peak serum concentrations of buspirone (about 40%) and 1-pyrimidinylpiperazine [1-PP, an active metabolite of buspirone] increased time to achieve peak serum concentrations of buspirone [about twofold]) and an increase in certain adverse buspirone effects (e.g., light-headedness) during combined use, but such changes were not considered clinically important.1,119,120,204 Because of considerable interindividual and intraindividual differences in some buspirone pharmacokinetic parameters observed in this study and problems in study design, however, some clinicians state that firm conclusions regarding the possibility of a clinically important interaction between buspirone and cimetidine currently cannot be made.120,186 The drugs also have been used concomitantly without evidence of a clinically important interaction in patients with anxiety,194 but additional study is necessary.120,186

Food !!navigator!!

Food may delay GI absorption of buspirone, thereby decreasing the extent of presystemic clearance of the drug (e.g., via first-pass metabolism in the liver)1,2,34,88 and increasing the amount of unchanged drug reaching systemic circulation.1,2,30,34,88 Following oral administration of a single 20-mg dose of buspirone hydrochloride with food, the area under the plasma concentration-time curve (AUC) and peak plasma concentration of unchanged buspirone increased by 84 and 116%, respectively, compared with administration in the fasted state, but the total amount of drug (changed and unchanged) in plasma was not affected.1,2,30,34,88 To minimize the variability in systemic exposure to buspirone, the manufacturer recommends that the drug should be given consistently with or without food.1

Alcohol !!navigator!!

Buspirone does not appear to alter blood alcohol concentrations50,51,73 nor to potentiate substantially alcohol-induced impairment of psychomotor and cognitive performance,1,2,5,10,34,48,50,51,55,73,74,76,90,93,105,112 and actually may produce some improvement in such impairment.10,51,74 In addition, patients receiving buspirone and alcohol may be more aware of alcohol-induced impairment, when present, than those receiving benzodiazepines and alcohol.50,73,93 It should be recognized, however, that subjective adverse effects, including fatigue,50,73 drowsiness,50,73 and dizziness,50 have occurred in some patients during administration of buspirone alone,50,73 and that adverse CNS effects associated with buspirone in individual patients may be unpredictable.1 In a controlled study in healthy adults, buspirone did not enhance alcohol-induced psychomotor impairment (as determined by objective measures such as lateral-gaze nystagmus, body sway, and the Maddox wing test), and subjective effects associated with concomitant buspirone and alcohol use were similar to those with buspirone alone.73 In another study in patients with a history of moderate to low-heavy alcohol use, driving-related motor skill performance was better in those given a single dose of alcohol after receiving buspirone for 9 days than in those given alcohol after receiving placebo.51 Although results of drug interaction studies suggest that buspirone does not potentiate substantially alcohol-induced psychomotor and cognitive impairment,1,2,5,10,34,48,51,55,73,74,76,90,93,105,112 patients should be advised that it would be prudent to avoid concomitant use.1,2,93,123

Other CNS Depressants !!navigator!!

Buspirone appears to interact minimally, if at all, with benzodiazepines.2,5,34,48,63,76,81,91,93,112,123,129 In a multiple-dose study, the addition of buspirone in patients receiving diazepam for 11 days did not substantially alter plasma diazepam concentrations measured on day 22 (11 days after initiating buspirone therapy), but corresponding plasma nordiazepam concentrations increased by approximately 20%.2,34,112,129 It is not known whether the increase in nordiazepam concentrations resulted from the relatively long time required for the metabolite to achieve steady-state plasma concentrations or from concomitant buspirone administration.34 In patients concurrently receiving buspirone and diazepam, mild adverse effects, including headache, nausea, dizziness, and muscle twitches, occurred but usually subsided within several days;34,129 however, such effects, except muscle twitches, appeared qualitatively similar to those associated with buspirone alone.2,34 Buspirone has potentiated the effects of diazepam on several tests of psychomotor function (e.g., the Maddox wing and letter cancellation tests) and has subjectively potentiated diazepam-induced sedation, but the drug also has counteracted diazepam-induced impairment of divided attention and learning acquisition; the combined effect of these drugs on psychomotor function did not appear to be more harmful than diazepam alone.76 Buspirone did not substantially alter the hypnotic or psychomotor effects of either flurazepam or triazolam when the drugs were administered concurrently in a limited number of patients, although a minimal decrease in card-sorting ability occurred in some patients.48,63,93,112,123 Although drug interaction studies suggest that buspirone does not potentiate benzodiazepine-induced CNS depression to a clinically important degree,2,5,34,48,63,76,81,91,93,112,123,129 the effects of combined therapy have not been fully evaluated to date.1 Pending further accumulation of data, benzodiazepines should be used with caution in patients receiving buspirone.1,105

Data obtained from clinical studies indicate that other CNS depressants, including analgesics, antihistamines, and sedative/hypnotics, generally have little or no effect on the frequency or severity of adverse effects associated with buspirone.2,5,34,48,63,76,81,91,93,105,112,123,129 It should be recognized, however, that subjective adverse effects, including fatigue,50,73 drowsiness,50,73 and dizziness,50 have been reported in some patients receiving buspirone alone,50,73 and that adverse CNS effects associated with buspirone in individual patients may be unpredictable.1 Because the effects of concurrent administration have not been fully evaluated to date, caution should be exercised when buspirone and CNS depressants are administered concomitantly.1,105

Other Information

[Section Outline]

Acute Toxicity

Limited information is available on the acute toxicity of buspirone.1,2

Pathogenesis !!navigator!!

The acute lethal dose of buspirone in humans is not known.1,2 The oral LD50 of the drug is 655, 196, 586, and 356 mg/kg in mice, rats, dogs, and monkeys, respectively.1,2

Manifestations !!navigator!!

A few cases of overdosage of buspirone have been reported; usually, all patients had complete recovery and no fatalities have been reported after overdosage of buspirone alone.1 In general, overdosage of buspirone may be expected to produce effects that are mainly extensions of pharmacologic and adverse effects.1,2 In clinical pharmacology studies in healthy adults, nausea, vomiting, dizziness, drowsiness, miosis, and gastric distension predominated as oral dosage approached 375 mg daily.1

Treatment !!navigator!!

There is no specific antidote for buspirone intoxication,1 and treatment of overdosage with the drug generally involves symptomatic and supportive care.1 Following acute ingestion of buspirone, the stomach should be emptied immediately by inducing emesis or by gastric lavage.1 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.117 Pulse, blood pressure, and respiration should be monitored.1

Chronic Toxicity

Buspirone appears to have little, if any, potential for tolerance or psychologic and/or physical dependence.1,2,6,52,55,75,77,84,87,92,98,112,123,124,184 In animal studies, there was no evidence of abuse potential or dependence liability.1,2,6,52,75,77,85,92,112,123,124,184 In studies in individuals with a history of recreational drug or chronic alcohol abuse, single 10-mg buspirone hydrochloride doses were neither euphoric nor dysphoric,52,84,92 and the drug's effects were indistinguishable from placebo.1,2,51,52,92 In addition, such individuals preferred methaqualone or diazepam to buspirone1,2,52,92 and experienced dysphoria and other unpleasant effects when single 40-mg buspirone hydrochloride doses were administered.52,55,84,92,112 Dysphoria also has occurred in healthy nonabusers during initiation of buspirone hydrochloride 20 mg daily.96,122 The dysphoric potential of buspirone and absence of euphoria observed in these individuals indicates that the drug has little, if any, abuse potential.52,84,92,112 However, it is difficult to predict from animal and human studies the extent to which a CNS-active drug like buspirone will be misused, diverted, and/or abused once it is marketed,1,122,123,159 and additional long-term experience is necessary to confirm findings of these studies.55,112,123,124,159,184,186

There has been no substantial evidence to date of a withdrawal syndrome associated with sudden discontinuance of buspirone therapy.39,83,87,92,98,112,122,123,124,184,191 Discontinuance of the drug after 6 or 12 weeks of 5-20 mg daily in patients with anxiety disorders was not associated with manifestations suggestive of withdrawal.83,87,92,98,112 In addition, substantial evidence of rebound anxiety or withdrawal was not observed following abrupt discontinuance of buspirone therapy in patients with anxiety disorders receiving an average of 27 mg of the drug daily for 6 months, although manifestations of withdrawal occurred following discontinuance of 6 months of clorazepate dipotassium at an average dosage of 33 mg daily.2,82,92,112,124,184 There also was no evidence of resorting to a reserve supply of drug, intended to counter serious or intolerable symptoms, following abrupt discontinuance of buspirone, while 40% of patients receiving clorazepate required doses of the benzodiazepine following discontinuance.184

Despite the absence of substantial evidence for abuse potential or dependence liability, clinicians should carefully evaluate patients for a history of substance abuse prior to initiating buspirone therapy.1 If buspirone is initiated in patients with a history of substance abuse, they should be monitored closely for signs of misuse or abuse of the drug (e.g., development of tolerance, use of increasing doses, drug-seeking behavior).1 In addition, it should be recognized that the potential for developing withdrawal following abrupt discontinuance of high dosages of buspirone hydrochloride (e.g., greater than 40 mg daily) or after prolonged therapy (e.g., longer than 6 months) has not been fully elucidated, and additional experience with chronic buspirone therapy is necessary.124

Pharmacology

Nervous System Effects !!navigator!!

The principal pharmacologic effect of buspirone is anxiolysis.1,2,4,5,6,7,8,10,11,12,13,14,15,16,20,32,37,68,70,78,112 Buspirone has been described as an anxioselective drug4,5,7,9,11,12,13,22,24,48,70,78,79,88,112,133,163 since, unlike benzodiazepines, it has no anticonvulsant1,2,6,9,11,12,13,16,18,22,68,70,78,88,112,133,163,176 or muscle relaxant1,2,6,9,11,12,13,22,68,70,78,79,88,112,163,176 activity, does not substantially impair psychomotor function,11,13,70,73,74,76,78,90,112,133 and has little sedative effect.1,2,6,9,11,13,16,18,22,40,41,45,48,61,62,78,112,133,163 Buspirone's anxiolytic potency is approximately equivalent to that of diazepam on a weight basis following oral administration.2,13,36,37,40,68,70

The precise mechanism of buspirone's anxiolytic action is not known but appears to be complex and distinct from benzodiazepines,1,2,4,5,6,7,8,11,12,13,15,16,68,70,78,88,112,131,133,163,177,187 and probably involves several central neurotransmitter systems.1,2,5,6,7,8,9,12,15,68,70,78,88,112,133,187 Likewise, a variety of sites in the CNS have been postulated as contributing to the anxiolytic action of the drug.1,2,5,6,7,8,9,12,15,68,70,78,101,103,112,133,138,140,141,143,144 Because of the variety and location of the drug's effects on central neurotransmitter systems, including serotonergic,1,2,5,6,7,8,9,10,11,15,68,69,70,78,88,101,102,103,112,133,135,136,137,138,139,140,141,142,143,144,146,147,148,149,163,182,187,190 dopaminergic,1,2,4,5,6,7,8,9,11,12,13,14,15,16,17,18,19,20,24,32,66,68,70,78,79,88,111,112,133,163 cholinergic,12,24,32,78,88 and noradrenergic (α-adrenergic) systems,5,7,9,11,12,15,22,23,68,70,78,88,112,133,163,182 buspirone has been described as a midbrain modulator.5,11,12,15,79,88

Buspirone has no appreciable affinity for the benzodiazepine receptor complex,1,2,6,11,14,15,16,66,78,79,112,133 nor does it inhibit or stimulate benzodiazepine binding at the receptor complex in vitro,1,2,6,7,8,12,13,16,18,70,88,112,149 although binding may be stimulated in vivo.12,21,32,66,70,78,112,133,163 Buspirone also does not appear to directly affect γ-aminobutyric acid (GABA) binding in vitro1,2,6,12,13,14,15,16,18,68,70,78,79,88,112,149 or in vivo.1,2,13,112 In vitro radioligand studies indicate that buspirone does not directly affect cholinergic (muscarinic),2,6,12,13,19,24,28,68,79α-adrenergic,2,6,12,13,19,22,28,66,68,79 type 2 serotonergic (5-HT2),2,12,13,19,68,112,182β-adrenergic,13,19,22,28 histamine (H1 or H2),2,6,12,13,28,68,78,79 opiate,2,6,13,28,68,78,79 adenosine (A1 or A2),6,15,28,68,78,79 glutamate,6,13,28,68,78,79 or glycine6,13,68,78,79 receptors or uptake of dopamine,6,78,79 GABA,6,13,78,79,88 norepinephrine,6,78,79 or serotonin.6,7,78,79,150 The drug does exhibit high affinity for type 1 serotonergic (5-HT1) receptors1,2,5,8,10,68,101,102,103,139,142,143,144,147,151,172,187 and moderate affinity for dopamine D21,2,4,6,12,13,14,15,16,19,20,22,28,68,79,106,111,123,187 receptors in vitro.

Serotonergic Effects

The contribution of the serotonergic system to anxiety has not been fully characterized,5,7,8,9,15,78,89,101,103,134,144 and the extent to which the anxiolytic action of buspirone might depend on this neurotransmitter system has not been fully elucidated.5,8,9,10,11,15,17,78,89,103,136,138,140,141,143,144,187,190 It has been suggested that serotonergic mechanisms may play a predominant role in the drug's anxiolytic activity;8,89,138,139,140,141,144,185,186,187 however, because of conflicting evidence,145,146 additional study is needed to establish the role of serotonergic receptors in mediating anxiolysis.7 The anticonflict effect of the drug has been shown to be reduced in serotonin-depleted animals.8,68,78,135,187 In addition, buspirone has been shown to inhibit spontaneous firing of serotonergic neurons in the dorsal raphe nucleus,2,68,69,78,132,138,140,141,171 an effect that also is exhibited by benzodiazepines78,134 and may be related to anxiolytic activity,134,138,140,141 and to inhibit stress-induced renin secretion that is mediated by serotonin.136

Buspirone has a high affinity for 5-HT1 receptors in the CNS,1,2,5,8,10,68,101,102,103,139,142,143,144,147,151,172,182,187 and appears to have a higher relative affinity for the 5-HT1A site on this receptor than for the 5-HT1B site.1,2,101,102,103,137,151,190 Buspirone appears to act as a partial agonist103,142,185,186,187 or mixed agonist/antagonist at this receptor,103,143,190 and there is some evidence to suggest that such activity may be associated with anxiolysis.101,103,143,144,187 Although buspirone has failed to induce the serotonin behavioral syndrome in some animal studies,7,8,20 the drug has exhibited agonist properties by inducing the syndrome in other studies that focused on 5-HT1- rather than 5-HT2-mediated behaviors;103 differences in methodology and interpretation and lack of insight regarding characterization of serotonin receptor subtypes and associated behaviors likely contributed to these discrepancies.102,103 It also has been suggested that agonist activity at the 5-HT1A receptor may be associated with antidepressant activity.147,148

Reports of buspirone's effects on serotonin metabolism have been conflicting.11,112 The drug has been reported to decrease2,9,11,112 or have no effect14 on striatal concentrations of serotonin and its principal metabolite, 5-hydroxyindoleacetic acid (5-HIAA), to decrease149 or have no effect11 on hippocampal serotonin and 5-HIAA concentrations, and to decrease serotonin20 but not 5-HIAA11 concentrations in the frontal cortex.

Dopaminergic Effects

The effects of buspirone on the dopaminergic neurotransmitter system are complex and have not been clearly elucidated.4,6,9,27,68,89,106,131,162,180 The drug appears to possess mixed dopamine agonist and antagonist activities.4,6,7,16,27,106,131,162,177 Buspirone may act as an agonist at postsynaptic dopamine receptor sites4,20,27,28,88,106,112 and as an antagonist at both presynaptic autoreceptor2,5,11,16,20,68,106,173 and postsynaptic sites.16,106,179 The relative contribution of these effects to the anxiolytic activity and toxic potential of the drug has not been clearly established and requires additional study.6,9,106,112,163,165,195

Buspirone has moderate affinity for dopamine D2 receptors in the CNS.1,2,4,6,12,13,14,15,19,20,22,28,68,79,89,106,111,123,187 Unlike most antipsychotic agents,2,11,16,179 buspirone appears to preferentially block presynaptic dopamine autoreceptors rather than postsynaptic D2 receptors in the striatum.2,5,11,12,16,20,68,106,173,179 The resultant buspirone-induced increases in dopamine metabolism2,6,9,12,14,16,20,32,68,106,112,173 and impulse formation,6,16,20,68,106,161,179 however, appear to resemble those of antipsychotic agents.32,106,173,180 The drug reportedly stimulates dopamine metabolism in a dose-related manner,2,6,9,16,20,68,106 and has increased striatal concentrations of the dopamine metabolites, 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC).2,6,9,12,14,16,20,32,68,112,173 Buspirone also has been reported to increase tyrosine 3-monooxygenase (tyrosine hydroxylase) activity in the striatum but not in the frontal cortex, which appears to lack autoreceptors,2,12,16,68,106 and has blocked apomorphine-induced inhibition of this enzyme.16,106 Unlike benzodiazepines but like butyrophenones (e.g., haloperidol), buspirone enhances spontaneous firing of dopaminergic neurons.6,16,20,68,106,161,179 Such effects on dopamine metabolism and impulse flow are consistent with presynaptic autoreceptor blockade.2,16,20,68

There is some evidence from animal studies that buspirone may act as an antagonist at postsynaptic D2 receptors and potentially may possess antipsychotic activity;4,6,11,13,26,28,68,163,166,176 the drug has inhibited conditioned avoidance behavior,6,13,26,68,163,166,176 blocked apomorphine-induced stereotypy6,7,13,68,163,166 and emesis,6,13,166 and blocked amphetamine-induced stereotypy.26 However, unlike most antipsychotic agents, buspirone does not induce catalepsy in animals,2,4,6,9,11,13,16,20,32,68,106,123,131,164 indicating that the drug may not produce substantial postsynaptic D2 blockade usually associated with antipsychotic activity.2,16,20,68,106 Although buspirone reportedly has produced transient antipsychotic effects when administered in large dosages (e.g., 600-2400 mg daily) to humans,26 the drug has no established clinical antipsychotic efficacy at usual anxiolytic dosages.1,2,4,6,11,13,26,106 The failure of buspirone to induce catalepsy in animal studies2,4,6,9,11,13,16,20,32,68,106,123,131,164 also suggests that the risk of drug-induced extrapyramidal reactions is minimal.6,68,123,131 No definitive extrapyramidal reactions have been attributed directly to buspirone therapy at usual anxiolytic dosages to date,2,123,185,191 although such reactions (e.g., akathisia,1,2,185,195 hypertonia,185 dystonia,195 tremor)185 reportedly have been associated with anxiolytic therapy with the drug in a few patients and also have occurred in at least one patient receiving a large dosage for potential antipsychotic effects.26 Unlike most antipsychotic agents, buspirone does not produce postsynaptic receptor supersensitivity following long-term therapy and has reversed such supersensitivity induced by antipsychotic agents; therefore, the drug appears unlikely to produce tardive dyskinesia.2,11,12,14,18,68,123 However, additional clinical experience is needed to determine buspirone's potential for inducing dopamine-mediated neurologic sequelae with long-term use.1,2,58,113,123,128 (See Cautions: Nervous System Effects and also Precautions and Contraindications.) Buspirone has been shown to produce a dose-dependent elevation in plasma prolactin concentrations (see Neuroendocrine Effects),27,28,49,88,111 possibly mediated by postsynaptic dopamine receptor blockade in the pituitary gland.27,28,88,111

Buspirone appears to possess some dopamine agonist activity.4,6,13,20,27,28,112,163 Like apomorphine, buspirone produces weak turning behavior in lesioned animals4,6,163 and, like amantadine, potently reverses catalepsy induced by antipsychotic agents,4,6,11,16,20,68,112,163,164 suggesting that the drug has some dopamine agonist activity.4,6,20,28,112 Buspirone reportedly elevates plasma somatotropin (growth hormone) concentrations (see Neuroendocrine Effects),27,88 an effect possibly mediated by postsynaptic dopamine agonist activity in the hypothalamus.27,88

Effects on GABA and the Benzodiazepine Receptor Complex

Buspirone has no appreciable affinity for the GABA-benzodiazepine-chloride ionophore receptor complex,1,2,6,7,11,12,14,15,16,66,78,79,112,133,149 and does not appear to inhibit or stimulate binding of benzodiazepines at the receptor complex in vitro,1,2,6,7,8,12,13,16,18,70,88,112,149 although binding may be stimulated in vivo.12,21,32,66,70,78,112,133,163 It is not known whether the increase in in vivo benzodiazepine binding observed in some studies reflects a change in the number of binding sites or an increase in receptor affinity.32,163 Buspirone does not appear to directly affect GABA binding in vitro1,2,6,12,13,14,15,16,18,68,70,78,79,88,112,149 or in vivo,1,2,13,112 and does not influence uptake of GABA.6,13,78,79,88 Benzodiazepine antagonists do not appear to block the anticonflict action of buspirone, suggesting that the drug does not exert its anxiolytic effect by directly affecting benzodiazepine receptors.12,21,66,163

Buspirone or an active metabolite may indirectly affect some component of the GABA-benzodiazepine-chloride ionophore receptor complex other than the benzodiazepine or GABA binding site, such as picrotoxin-sensitive chloride ionophore segments.12,88,163 It has been suggested that the drug may have a picrotoxin-like antagonistic effect on presynaptic GABA receptors, thereby enhancing GABA transmission;12 however, inhibitory effects of GABA on impulse flow do not appear to be altered by the drug.178 Further study is required to determine whether there is an association between buspirone's effects on the benzodiazepine receptor complex and the anticonflict and anxiolytic actions of the drug.12,66,163

Adrenergic Effects

Buspirone does not appear to have a direct effect on α1-, α2-, or β-adrenergic receptors in vitro,2,6,12,13,16,19,22,28,66,68,79 and has no apparent effect on biogenic amine uptake, including norepinephrine.6,22,78,79,132 The drug does, however, appear to exhibit weak central α-adrenergic blocking activity in vivo.4,9,131,166 Limited evidence suggests that 1-pyrimidinylpiperazine (1-PP), a metabolite of buspirone, possesses central and peripheral α2-adrenergic blocking activity, which may contribute to the drug's anxiolytic and/or antidepressant effects.178,182,183 Unlike benzodiazepines, which inhibit spontaneous firing of noradrenergic neurons in the locus ceruleus and decrease norepinephrine metabolism in the brain,2,5,16,22,132,178 buspirone and its metabolite 1-PP enhance neuronal activity in the locus ceruleus and increase norepinephrine metabolism,2,5,16,22,132,178 suggesting that a reduction in locus ceruleus output is not a prerequisite for anxiolytic activity.22,178 It has been suggested that buspirone-induced facilitation of noradrenergic neuronal firing may contribute to alertness and alleviate any benzodiazepine-like impairment of psychomotor performance, thereby preserving arousal and attentional processes.2 The drug has been shown to decrease striatal concentrations of norepinephrine and to increase striatal concentrations of 3-methoxy-4-hydroxyethylenephenylglycol (MOPEG, MHPG), a major metabolite of norepinephrine.132 The drug does not appear to alter monoamine oxidase (MAOA or MAOB) activity.7

Cholinergic Effects

Buspirone does not appear to directly affect cholinergic receptors,2,6,12,13,19,24,28,68,79,149 but the drug's effects on the cholinergic neurotransmitter system and their relationship with the dopaminergic neurotransmitter system have not been fully elucidated to date.24 Like antipsychotic agents but unlike benzodiazepines,24,32,106 the drug decreases striatal concentrations of acetylcholine;2,12,20,24,32 the activity of acetylcholinesterase or choline acetyltransferase does not appear to be affected.2,24 There is some evidence that buspirone-induced decreases in acetylcholine concentrations may be dopaminergically mediated.24 The drug has enhanced the effects of cholinergic agonists on cholinergically induced catalepsy when administered at doses that decrease striatal acetylcholine concentrations.2 Buspirone does not protect against physostigmine-induced lethality in animals6 and appears to lack clinically important anticholinergic activity in humans.6,131

Effects on Sleep

Buspirone does not appear to possess clinically important sedative/hypnotic activity.2,6,48,112,123,133,171 At usual anxiolytic dosages, the drug does not appear to affect sleep (e.g., sleep pattern or efficiency, total wake time, number of awakenings) substantially in patients with mild2,123 or chronic48,112 insomnia but without underlying anxiety, although decreased total rapid eye movement (REM) time and increased REM onset time may occur.48,112 In anxious patients, buspirone may produce subjective improvement in quality of sleep, secondary to the drug's anxiolytic action, without accompanying hypnotic and/or sedative effects.2 In animals, buspirone has increased sleep latency and total sleep time while decreasing both REM and nonREM sleep.171 Although not clearly established, the increase in wakefulness and decrease in sleep observed in animals may be serotonergically mediated,171 since the drug has been shown to inhibit firing of serotonergic neurons in the dorsal raphe nucleus.2,68,69,78,138,140,141,171

Other Nervous System Effects

Unlike benzodiazepines, buspirone produces anxiolysis1,2,4,5,6,7,8,10,11,12,13,14,15,16,20,32,37,68,70,78,112 without causing substantial impairment of psychomotor function2,11,13,70,73,74,76,78,90,112,133 or sedation.1,2,6,9,11,13,16,18,22,40,41,45,48,61,62,78,112,133,163 In addition, buspirone lacks anticonvulsant activity1,2,6,9,11,12,13,22,68,70,78,79,88,112,163,176 and appears to have little effect on the EEG.43,49,96 The drug has increased fast-wave activity slightly at a dosage of 15 mg daily and decreased fast-wave activity at 30 mg daily, but these changes were not considered clinically important.43

Neuroendocrine Effects !!navigator!!

Buspirone appears to cause a dose-related increase in prolactin secretion,27,28,49,88,111,112 possibly via postsynaptic dopamine receptor blockade in the pituitary gland.27,28,88,111 The drug has increased plasma prolactin concentrations at single oral doses ranging from 25-100 mg,27,88,111 but substantial alterations in prolactin secretion were not apparent at lower doses.53,88 Long-term oral administration of buspirone hydrochloride at a dosage of 30 mg daily also does not appear to be associated with substantial alterations in prolactin secretion.53

Buspirone can increase plasma somatotropin (growth hormone) concentrations,27,88 an effect possibly mediated by postsynaptic dopamine agonist activity in the hypothalamus.27,88 Single 30- to 90-mg oral doses of the drug have been associated with substantial, although not dose-related, increases in somatotropin concentrations;27,88 substantial alterations were not apparent at lower doses.53,88 Long-term oral administration of buspirone hydrochloride dosages of 30 mg daily also does not appear to be associated with substantial alterations in plasma somatotropin concentrations.53,112

Cardiovascular Effects !!navigator!!

Buspirone appears to cause minimal cardiovascular effects when administered at usual anxiolytic dosages.2,174 (See Cautions: Cardiovascular Effects.) Clinically important ECG changes and changes in vital signs generally do not occur during therapy with the drug.2 Tachycardia and/or palpitation1,2,61 and nonspecific chest pain have been reported in some patients receiving buspirone,1,2,61 although a causal relationship has not been established.185,186 Buspirone possesses only weak α1-adrenergic blocking activity4,9,131,166 and therefore is not expected to cause clinically important hypotension.4,131 In addition, although limited evidence in animals receiving high doses of the drug suggests that buspirone may possess some peripheral vascular postsynaptic α1-adrenergic agonist activity, clinically important cardiovascular effects do not appear likely at usual anxiolytic doses.174

Other Effects !!navigator!!

Limited data from healthy adults receiving single, 10-mg oral doses suggest that buspirone does not substantially depress the ventilatory response to carbon dioxide (CO2) stimulation; however, additional study is necessary to more fully determine the drug's effects on respiration.188

Pharmacokinetics

The pharmacokinetics of buspirone hydrochloride have been studied in healthy adults, geriatric patients, and in patients with renal or hepatic impairment.1 Single- and multiple-dose studies of buspirone have not revealed gender- or age-related differences in the pharmacokinetics (e.g., area under the plasma-concentration time curve [AUC], peak plasma concentrations) of the drug. Pharmacokinetics of buspirone hydrochloride with respect to race have not been determined.1

Absorption !!navigator!!

Buspirone hydrochloride is rapidly1,2,4,5,29,34,64,88 and almost completely2,34,64,112,116 absorbed from the GI tract. However, the drug undergoes extensive first-pass metabolism,1,2,4,31,34,64,112,116 with only about 4% (range: 1.5-13%) of a dose reaching systemic circulation unchanged following oral administration.2,31,34,104,112,116 The relative oral bioavailability of buspirone hydrochloride tablets reportedly is about 90% that of a solution of the drug;1,185 a lower relative bioavailability (i.e., 65%) has been reported for another tablet formulation of the drug that is not commercially available.2,185 Food may delay GI absorption of buspirone hydrochloride, thereby decreasing the extent of presystemic clearance of the drug1,2,34 and increasing the amount of unchanged buspirone reaching systemic circulation.1,2,5,30,34 (See Drug Interactions: Food.) Following multiple-dose administration of buspirone in patients with renal impairment (creatinine clearance of 10-70 mL/minute per 1.73 m2), the steady-state AUC was increased fourfold compared with healthy adults (creatinine clearance of 80 mL/minute per 1.73 m2 or more).1 Following multiple-dose administration in patients with hepatic impairment, steady-state AUC of buspirone was increased 13-fold compared with healthy adults.1 AUC and peak plasma concentration of unchanged buspirone are increased substantially in patients with liver cirrhosis, exceeding those achieved in healthy adults by about 16-fold in one study following a single, 20-mg oral dose.110

Following oral administration of a single 20-mg dose in healthy individuals, peak plasma buspirone concentrations of 1-6 ng/mL occur within 40-90 minutes.1,2,4,29,31,34,64,65,115 Peak plasma concentrations of the drug averaged 0.9, 1.7, and 3.2 ng/mL following single oral doses of 10, 20, and 40 mg, respectively, in a study in healthy adults.2,29,115 Plasma concentrations of unchanged buspirone exhibit interindividual variation following oral administration of the drug1 but generally are low, averaging about 1% of the total plasma drug concentration in one study in fasting, healthy adults receiving single doses of the drug.1,34,185 Although it has been suggested that the drug exhibits nonlinear pharmacokinetics and that increasing and/or multiple doses may result in higher plasma concentrations than those predicted from single-dose studies,1 this interpretation of the drug's pharmacokinetics has been questioned.29,115,185 In addition, in a study in healthy adults, the relationship between plasma buspirone concentration and dose appeared to be linear at single oral doses ranging from 10-40 mg.29,115,185 Following oral administration of buspirone hydrochloride, the onset of anxiolytic activity may be apparent within the first 2 weeks of therapy,38,123 but optimum therapeutic effect usually requires at least 3-4 weeks;39,41,123 occasionally, 4-6 weeks may be required for optimum effect.87 The relationship, if any, between plasma buspirone and active metabolite concentrations and the therapeutic and/or toxic effects of the drug have not been established.185,186

Distribution !!navigator!!

Distribution of buspirone into human body tissues and fluids has not been well characterized.5,112 Following IV administration in rats, buspirone is extensively distributed, achieving highest concentrations in lung, kidney, and adipose tissue, and lower concentrations in skeletal muscle, heart, liver, brain, and plasma.112,127 The concentration-time curve profiles of buspirone and its active metabolite 1-pyrimidinylpiperazine (1-PP) in brain almost parallel those in plasma after oral31,32 or IV32 administration, although 1-PP concentrations generally are higher in brain than in plasma, particularly following oral administration of the drug.15,31,32,112,126 In animals, 1-PP accumulates in the brain and reaches concentrations that are approximately 4-5 times higher than those in plasma.5,15,31,32,112 The apparent volume of distribution of buspirone in healthy adults reportedly averages 5.3 L/kg following a single IV dose.34,112,116

Buspirone is approximately 86-95% bound to plasma proteins in vitro,1,2,34,104,203 mainly to albumin and, to a lesser extent, α1-acid glycoprotein (α1-AGP).34,35

Buspirone and its metabolites are distributed into milk in animals.1,123 It is not known whether the drug distributes into milk in humans.1,123,185

Elimination !!navigator!!

Following single oral doses of 10-40 mg in healthy adults, the elimination half-life of buspirone averages about 2-4 hours (range: 2-11 hours).1,2,4,15,29,31,34,65,104,110,112,115,116 The elimination half-life of the drug appears to be slightly longer in females than in males, although the clinical importance of this difference has not been established.2,34,112 The elimination half-life does not appear to be affected by increases in dose2,29,34,112 or by concomitant administration with food,30 but may be prolonged in patients with renal impairment, particularly those with anuria,34,104 and in patients with liver impairment, including those with cirrhosis.1,34,110,112 In a limited number of patients with mild to moderate renal impairment (creatinine clearances of 60 mL/minute or less per 1.73 m2) or with anuria, the buspirone elimination half-life averaged 5.7 or 6.1 hours, respectively, while it averaged 4 hours in healthy individuals.34,104 Elimination half-life of the drug averaged 6.1 hours in a limited number of patients with liver cirrhosis following oral administration.110,185

Buspirone is metabolized extensively in the liver, mainly via oxidation by the cytochrome P-450 (CYP) isoenzyme 3A4, to form several hydroxylated metabolites, including 5-hydroxybuspirone (5-HB) and 1-pyrimidinylpiperazine (1-PP).1,4,5,15,31,32,34,64,112,125 5-Hydroxybuspirone is further oxidized to at least 2 additional hydroxy metabolites, which subsequently undergo conjugation.4,34,64,88 Following oral administration of a single 20-mg dose of buspirone hydrochloride in healthy adults, the elimination half-lives of 1-PP,31 5-HB,4,64,88 and the glucuronide of 5-HB4,64,88 have been reported to average about 6.1, 4.8, and 3.2 hours, respectively.4,31,64,88

The major pharmacologically active metabolite is 1-PP.1,5,15,31,32,33,34,112,125 In animals, 1-PP has about 20-25% of the anxiolytic activity of buspirone but is present in the brain in concentrations up to 15-to 30-fold greater than those of unchanged drug.1,2,34,112,125,129 In humans, however, blood concentrations of 1-PP remain relatively low even after chronic administration of buspirone,1 and the contribution of this metabolite to the pharmacologic and/or toxic effects of the drug has not been fully elucidated.2,5,15,31,32,34,112 In one study, blood 1-PP concentrations reportedly averaged 3 ng/mL during chronic oral administration and did not exceed 17 ng/mL, which is less than 0.5% of the 1-PP concentrations found in animals that were given large doses (50-200 mg/kg) of buspirone hydrochloride without exhibiting signs of toxicity.1 Unlike buspirone, 1-PP does not affect the dopaminergic system4,15,20,32,33 but does appear to possess some α2-adrenergic blocking activity, which may contribute to buspirone's anxiolytic and/or antidepressant effects.178,182,183

Buspirone and its metabolites are excreted principally in urine and, to a lesser extent, in feces.1,2,34,112 About 29-63% of a single oral dose of the drug is excreted in urine and about 18-38% in feces within 24 hours, mainly as metabolites.1,2,5,34,64,112,116 Buspirone appears to be excreted in urine almost completely as metabolites, with less than 0.1% of the total oral dose being excreted as unchanged drug.2,5,31,34,64,104,112 Fecal excretion of the drug appears to occur via biliary secretion.34

Following IV administration in healthy adults, total body clearance of buspirone from plasma averaged approximately 28 mL/minute per kg.34,116 Limited data suggest that elimination of unchanged buspirone is not altered substantially in patients undergoing hemodialysis, although plasma concentrations and elimination half-life of 1-PP may be reduced.104 The reduced clearance of 1-PP observed in anuric patients with chronic renal failure appears to be only partly reversed by hemodialysis.104 It is not known whether buspirone and/or its metabolites are removed by peritoneal dialysis.1

Chemistry and Stability

Chemistry !!navigator!!

Buspirone hydrochloride is an azaspirodecanedione-derivative anxiolytic agent.2,4,70,89,112,131,132,133 The drug also has been referred to as an arylpiperazine derivative.4,131,132,161,186,187 Buspirone differs structurally and pharmacologically from benzodiazepines, barbiturates, and other currently available anxiolytic agents.1,2,4,6,70,78,112,132,133,187 The heteroaryl piperazine nature of buspirone appears to be responsible for the drug's anxiolytic activity,132,187 serotonergic effects,187 and dopamine antagonist properties.4 Presence of the pyrimidinylpiperazine moiety as the heteroaryl component of buspirone's structure appears to be an important structural feature for the drug's anxiolytic activity132,187 and serotonergic effects,187 which may be related,187 and presence of this moiety also may contribute to the drug's relative lack of antipsychotic activity.4,131 Susceptibility of the drug to rapid and extensive 5-hydroxylation in vivo also may contribute to the relative lack of antipsychotic activity.4 Binding of the drug to dopamine receptors appears to depend on presence of the pyrimidinylpiperazine moiety, which can bind at several primary sites of the receptors, and on the azaspirodecanedione moiety, which can bind at a lipophilic accessory site of the receptors.4,131

Buspirone hydrochloride occurs as a white, crystalline powder1,2,5 and has solubilities of greater than 865 mg/mL in water2,4,5 and approximately 20 mg/mL in alcohol2 at 25°C.185 The manufacturer states that the drug has pKas of 1.22 and 7.32.2,185

Stability !!navigator!!

Buspirone hydrochloride tablets should be stored in tight, light-resistant containers at a temperature less than 30°C1,185 and have an expiration date of 36 months following the date of manufacture.3

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

busPIRone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

5 mg*

BuSpar® (scored)

Bristol-Myers Squibb

busPIRone Hydrochloride Tablets (scored)

7.5 mg*

busPIRone Hydrochloride Tablets

10 mg*

BuSpar® (multi-scored)

Bristol-Myers Squibb

busPIRone Hydrochloride Tablets (scored)

15 mg*

BuSpar® Dividose (scored)

Bristol-Myers Squibb

busPIRone Hydrochloride Tablets (multi-scored)

30 mg*

BuSpar® Dividose (multi-scored)

Bristol-Myers Squibb

busPIRone Hydrochloride Tablets (multi-scored)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb. BuSpar® (buspirone hydrochloride) prescribing information. Princeton, NJ; 2002 Feb.

2. Mead Johnson Pharmaceuticals. BuSpar® (buspirone hydrochloride) manufacturer's information. Evansville, IN; 1986 Dec.

3. Mead Johnson Pharmaceuticals. BuSpar® (buspirone hydrochloride) product information. Evansville, IN; (undated).

4. Temple DL Jr, Yevich JP, New JS. Buspirone: chemical profile of a new class of anxioselective agents. J Clin Psychiatry . 1982; 43(12 Part 2):4-10. [PubMed 6185470]

5. Kastenholz KV, Crismon ML. Buspirone, a novel nonbenzodiazepine anxiolytic. Clin Pharm . 1984; 3:600-7. [PubMed 6150781]

6. Riblet LA, Taylor DP, Eison MS et al. Pharmacology and neurochemistry of buspirone. J Clin Psychiatry . 1982; 43(12 Part 2):11-6. [PubMed 6130068]

7. Skolnick P, Weissman BA, Youdim MBH. Monoaminergic involvement in the pharmacological actions of buspirone. Br J Pharmacol . 1985; 86:637-44. [PubMed 2933109][PubMedCentral]

8. Eison AS, Eison MS, Stanley M et al. Serotonergic mechanisms in the behavioral effects of buspirone and gepirone. Pharmacol Biochem Behav . 1986; 24:701-7. [PubMed 2871564]

9. Hjorth S, Carlsson A. Buspirone: effects on central monoaminergic transmission—possible relevance to animal experimental and clinical findings. Eur J Pharmacol . 1982; 83:299-303. [PubMed 6129148]

10. Glaser T, Traber J. Buspirone: action on serotonin receptors in calf hippocampus. Eur J Pharmacol . 1983; 88:137-8. [PubMed 6133764]

11. Taylor DP, Allen LE, Becker JA et al. Changing concepts of the biochemical action oi the anxioselective drug, buspirone. Drug Dev Res . 1984; 4:95-108.

12. Eison MS, Eison AS. Buspirone as a midbrain modulator: anxiolysis unrelated to traditional benzodiazepine mechanisms. Drug Dev Res . 1984; 4:109-19.

13. Stanton HC, Taylor DP, Riblet LA. Buspirone—an anxioselective drug with dopaminergic action. In: Chronister RB, DeFrance IF, eds. The neurobiology of the nucleus accumbens (proceedings symposium). Brunswick, ME: Haer Institute; 1981:316-21.

14. Cimino M, Ponzio F, Achilli G et al. Dopaminergic effects of buspirone, a novel anxiolytic agent. Biochem Pharmacol . 1983; 32:1069-74. [PubMed 6838654]

15. Leonard BE. Neuropharmacological profile of buspirone: a nonbenzodiazepine anxiolytic with specific mid-brain modulating properties. Br J Clin Pract . 1985; 38(Symp Suppl):74-82.

16. McMillen BA, Matthews RT, Sanghera MK et al. Dopamine receptor antagonism by the novel anti-anxiety drug, buspirone. J Neurosci . 1983; 3:733-8. [PubMed 6131948]

17. Kaulen P, Brüning G, Schneider U et al. Autoradiographic localization of [3H]buspirone binding sites in rat brain. Neurosci Lett . 1985; 53:191-5. [PubMed 3982707]

18. McMillen BA. Comparative chronic effects of buspirone or neuroleptics on rat brain dopaminergic neurotransmission. J Neural Transm . 1985; 64:1-12. [PubMed 2866230]

19. Wood PL, Nair NPV, Lal S et al. Buspirone: a potential atypical neuroleptic. Life Sci . 1983; 33:269-73. [PubMed 6135133]

20. McMillen BA, Mattiace LA. Comparative neuropharmacology of buspirone and MJ-13805, a potential anti-anxiety drug. J Neural Transm . 1983; 57:255-65. [PubMed 6140299]

21. Oakley NR, Jones BJ. Buspirone enhances [3H]flunitrazepam binding in vivo. Eur J Pharmacol . 1983; 87:499-500. [PubMed 6133760]

22. Sanghera MK, McMillen BA, German DC. Buspirone, a non-benzodiazepine anxiolytic, increases locus coeruleus noradrenergic neuronal activity. Eur J Pharmacol . 1983; 86:107-10.

23. Kozak W, Valzelli L, Garattini S. Anxiolytic activity on locus coeruleus-mediated suppression of muricidal aggression. Eur J Pharmacol . 1984; 105:323-6. [PubMed 6150860]

24. Kolasa K, Fusi R, Garattini S et al. Neurochemical effects of buspirone, a novel psychotropic drug, on the central cholinergic system. J Pharm Pharmacol . 1982; 34:314-7. [PubMed 6123570]

25. Geller I, Hartmann RJ. Effects of buspirone on operant behavior of laboratory rats and cynomologus monkeys. J Clin Psychiatry . 1982; 43(12 Part 2):25-32. [PubMed 6130070]

26. Sathananthan GL, Sanghvi I, Phillips N et al. MJ 9022: correlation between neuroleptic potential and stereotypy. Curr Ther Res . 1975; 18:701-5. [PubMed 1208]

27. Meltzer HY, Flemming R, Robertson A. The effect of buspirone on prolactin and growth hormone secretion in man. Arch Gen Psychiatry . 1983; 40:1099-1102. [PubMed 6138009]

28. Meltzer HY, Simonovic M, Fang VS et al. Effect of buspirone on rat plasma prolactin levels and striatal dopamine turnover. Psychopharmacology . 1982; 78:49-53. [PubMed 6128756]

29. Gammans RE, Mayol RF, Mackenthun AV et al. The relationship between buspirone bioavailability and dose in healthy subjects. Biopharm Drug Dispos . 1985; 6:139-45. [PubMed 2860931]

30. Mayol RF, Gammans RE, Mackenthun AV et al. The effect of food on the bioavailability of buspirone hydrochloride. Clin Res . 1983; 31:631A.

31. Caccia S, Conti I, Vigano G et al. 1-(2-Pyrimidinyl)-piperazine as active metabolite of buspirone in man and rat. Pharmacology . 1986; 33:46-51. [PubMed 2874572]

32. Garattini S, Caccia S, Mennini T. Notes on buspirone's mechanisms of action. J Clin Psychiatry . 1982; 43(12 Part 2):19-22. [PubMed 6130069]

33. Garattini S. Active drug metabolites: an overview of their relevance in clinical pharmacokinetics. Clin Pharmacokinet . 1985; 10:216-27. [PubMed 2861928]

34. Gammans RE, Mayol RF, Labudde JA. Metabolism and disposition of buspirone. Am J Med . 1986; 80(Suppl 3B):41-51. [PubMed 3515929]

35. Bullen WW, Bivens DL, Gammans RE et al. The binding of buspirone to human plasma proteins. Fed Proc . 1985; 44:1123.

36. Feighner JP, Merideth CH, Hendrickson GA. A double-blind comparison of buspirone and diazepam in outpatients with generalized anxiety disorder. J Clin Psychiatry . 1982; 43(12 Part 2):103-7. [PubMed 6130066]

37. Goldberg HL, Finnerty RJ. The comparative efficacy of buspirone and diazepam in the treatment of anxiety. Am J Psychiatry . 1979; 136:1184-7. [PubMed 382878]

38. Jacobson AF, Dominguez RA, Goldstein BJ et al. Comparison of buspirone and diazepam in generalized anxiety disorder. Pharmacotherapy . 1985; 5:290-6. [PubMed 2866493]

39. Pecknold JC, Familamiri P, Chang H et al. Buspirone: anxiolytic? Prog Neuro Psychopharmacol Biol Psychiatry . 1985; 9:639-42. (IDIS 222145)

40. Goldberg HL, Finnerty R. Comparison of buspirone in two separate studies. J Clin Psychiatry . 1982; 43(12 Part 2):87-91. [PubMed 6759499]

41. Wheatley D. Buspirone: multicenter efficacy study. J Clin Psychiatry . 1982; 43(12 Part 2):92-4. [PubMed 6130079]

42. Cohn JB, Bowden CL, Fisher JG et al. Double-blind comparison of buspirone and clorazepate in anxious outpatients. Am J Med . 1986; 80(Suppl 3B):10-6. [PubMed 2870640]

43. Bond A, Lader M, Shrotriya R. Comparative effects of a repeated dose regime of diazepam and buspirone on subjective ratings, psychological tests and the EEG. Eur J Clin Pharmacol . 1983; 24:463-7. [PubMed 6134624]

44. Schweizer E, Rickels K, Lucki I. Resistance to the anti-anxiety effect of buspirone in patients with a history of benzodiazepine use. N Engl J Med . 1986; 314:719-20. [PubMed 2869408]

45. Cohn JB, Wilcox CS. Low sedation potential of buspirone compared with alprazolam and lorazepam in the treatment of anxious patients: a double-blind study. J Clin Psychiatry . 1986; 47:409-12. [PubMed 2874128]

46. Turnbull JM, Turnbull SK. Management of specific anxiety disorders in the elderly. Geriatrics . 1985; 40:75-82. [PubMed 4007503]

47. Napoliello MJ. An interim multicentre report on 677 anxious geriatric out-patients treated with buspirone. Br J Clin Pract . 1986; 40:71-3. [PubMed 2871858]

48. Seidel WF, Cohen SA, Bliwise NG et al. Buspirone: an anxiolytic without sedative effect. Psychopharmacology . 1985; 87:371-3. [PubMed 2867573]

49. Lader M. Psychological effects of buspirone. J Clin Psychiatry . 1982; 43(12 Part 2):62-7. [PubMed 6130075]

50. Seppala T, Aranko K, Mattila MJ et al. Effects of alcohol on buspirone and lorazepam actions. Clin Pharmacol Ther . 1982; 32:201-7. [PubMed 6124334]

51. Moskowitz H, Smiley A. Effects of chronically administered buspirone and diazepam on driving-related skills performance. J Clin Psychiatry . 1982; 43(12 Part 2):45-55. [PubMed 6130073]

52. Cole JO, Orzack MH, Beake B et al. Assessment of the abuse liability of buspirone in recreational sedative users. J Clin Psychiatry . 1982; 43(12 Part 2):69-74. [PubMed 6130076]

53. Cohn JB, Wilcox CS, Meltzer HY. Neuroendocrine effects of buspirone in patients with generalized anxiety disorder. Am J Med . 1986; 80(Suppl 3B):36-40. [PubMed 3963033]

54. Schweizer EE, Amsterdam J, Rickels K et al. Open trial of buspirone in the treatment of major depressive disorder. Psychopharmacol Bull . 1986; 22:183-5. [PubMed 2873610]

55. Meyer RE. Anxiolytics and the alcoholic patient. J Stud Alcohol . 1986; 47:269-73. [PubMed 2875216]

56. Frazer GA, Lapierre YD. The effect of buspirone on panic disorder: a case report. J Clin Psychopharmacol . 1987; 7:118-9. [PubMed 2884236]

57. Hammerstad JP, Carter J, Nutt JG et al. Buspirone in Parkinson's disease. Clin Neuropharmacol . 1986; 9:556-60. [PubMed 3026624]

58. Ludwig CL, Weinberger DR, Bruno G et al. Buspirone, Parkinson's disease, and the locus ceruleus. Clin Neuropharmacol . 1986; 9:373-8. [PubMed 2873889]

59. Napoliello MJ. A study of buspirone coprescribed with antidepressants in 184 anxious ambulatory patients. Curr Ther Res . 1986; 40:917-23.

60. Jerkovich GS, Preskorn SH. Failure of buspirone to protect against lorazepam withdrawal symptoms. JAMA . 1987; 258:204-5. [PubMed 2885432]

61. Newton RE, Marunycz JD, Alderdice MT et al. Review of the side-effect profile of buspirone. Am J Med . 1986; 80(Suppl 3B):17-21. [PubMed 2870641]

62. Newton RE, Casten GP, Alms DR et al. The side effect profile of buspirone in comparison to active controls and placebo. J Clin Psychiatry . 1982; 43(12 Part 2):100-2. [PubMed 6130065]

63. Schnabel T Jr. Evaluation of the safety and side effects of antianxiety agents. Am J Med . 1987; 82(Suppl 5A):7-13. [PubMed 2884874]

64. Gammans RE, Mayol RF, LaBudde JA et al. Metabolic fate of14C/15N-buspirone in man. Fed Proc . 1982; 41:1335.

65. Mayol RF, Marvel CJ, LaBudde JA. Development and validation of a radioimmunoassay for buspirone. Fed Proc . 1981; 40:684.

66. Weissman BA, Barrett JE, Brady LS et al. Behavioral and neurochemical studies on the anticonflict actions of buspirone. Drug Dev Res . 1984; 4:83-93.

67. Riblet LA, Allen LE, Hyslop DK et al. Pharmacologic activity of buspirone, a novel non-benzodiazepine antianxiety agent. Fed Proc . 1980; 39:752.

68. Eison AS, Temple DL Jr. Buspirone: review of its pharmacology and current perspectives on its mechanism of action. Am J Med . 1986; 80(Suppl 3B):1-9. [PubMed 2870639]

69. VanderMaelen CP, Wilderman RC. Iontophoretic and systemic administration of the non-benzodiazepine anxiolytic drug buspirone causes inhibition of serotonergic dorsal raphe neurons in rats. Fed Proc . 1984; 43:947.

70. Taylor DP, Eison MS, Riblet LA et al. Pharmacological and clinical effects of buspirone. Pharmacol Biochem Behav . 1985; 23:687-93. [PubMed 2866549]

71. Schweizer E, Rickels K. Failure of buspirone to manage benzodiazepine withdrawal. Am J Psychiatry . 1986; 143:1590-2. [PubMed 2878622]

72. Rickels K, Weisman K, Norstad N et al. Buspirone and diazepam in anxiety: a controlled study. J Clin Psychiatry . 1982; 43(12 Part 2):81-6. [PubMed 6130078]

73. Mattila MJ, Aranko K, Seppala T. Acute effects of buspirone and alcohol on psychomotor skills. J Clin Psychiatry . 1982; 43(12 Part 2):56-60. [PubMed 6130074]

74. Erwin CW, Linnoila M, Hartwell J et al. Effects of buspirone and diazepam, alone and in combination with alcohol, on skilled performance and evoked potentials. J Clin Psychopharmacol . 1986; 6:199-208. [PubMed 3734141]

75. Eison MS. Lack of withdrawal signs of dependence following cessation of treatment or Ro-15,1788 administration to rats chronically treated with buspirone. Neuropsychobiology . 1986; 16:15-8. [PubMed 3106850]

76. Mattila M, Seppala T, Mattila MJ. Combined effects of buspirone and diazepam on objective and subjective tests of performance in healthy volunteers. Clin Pharmacol Ther . 1986; 40:620-6. [PubMed 3780124]

77. Balster RL, Woolverton WL. Intravenous buspirone self-administration in rhesus monkeys. J Clin Psychiatry . 1982; 43(12 Part 2):34-7. [PubMed 6130071]

78. Riblet LA, Eison AS, Eison MS et al. Neuropharmacology of buspirone. Psychopathology . 1984; 17(Suppl 3):69-78. [PubMed 6150510]

79. Riblet LA, Eison AS, Eison MS et al. Buspirone: an anxioselective alternative for the management of anxiety disorders. Prog Neuro-Psychopharmacol & Biol Psychiatry . 1983; 7:663-8.

80. Anon. Drugs for psychiatric disorders. Med Lett Drugs Ther . 1986; 28:99-106. [PubMed 3762490]

81. Rickels K. Nonbenzodiazepine anxiolytics: clinical usefulness. J Clin Psychiatry . 1983; 44:38-43. [PubMed 6139368]

82. Rickels K. Clinical studies of "specific" anxiolytics as therapeutic agents. Psychopharmacol Ser . 1987; 3:88-95. [PubMed 2881295]

83. Anon. Buspirone: a non-benzodiazepine for anxiety. Med Lett Drugs Ther . 1986; 28:117-8. [PubMed 2878352]

84. Griffith JD, Jasinski DR, Casten GP et al. Investigation of the abuse liability of buspirone in alcohol-dependent patients. Am J Med . 1986; 80(Suppl 3B):30-5. [PubMed 3963032]

85. File SE. Aversive and appetitive properties of anxiogenic and anxiolytic agents. Behav Brain Res . 1986; 21:189-94. [PubMed 2876714]

86. Lader M, Olajide D. A comparison of buspirone and placebo in relieving benzodiazepine withdrawal symptoms. J Clin Psychopharmacol . 1987; 7:11-5. [PubMed 2880872]

87. Tyrer P, Murphy S, Owen RT. The risk of pharmacological dependence with buspirone. Br J Clin Pract . 1985; 38(Symp Suppl):91-3.

88. Goldberg HL. Buspirone hydrochloride: a unique new anxiolytic agent. Pharmacokinetics, clinical pharmacology, abuse potential and clinical efficacy. Pharmacotherapy . 1984; 4:315-24. [PubMed 6151170]

89. Jann MW. Buspirone: an update on a unique anxiolytic agent. Pharmacotherapy . 1988; 8:100-16. [PubMed 3041384]

90. Smiley A, Moskowitz H. Effects of long-term administration of buspirone and diazepam on driver steering control. Am J Med . 1986; 80(Suppl 3B):22-9. [PubMed 3963031]

91. Gershon S. Drug interactions in controlled clinical trials. J Clin Psychiatry . 1982; 43(12 Part 2):95-8. [PubMed 6130080]

92. Lader M. Assessing the potential for buspirone dependence or abuse and effects of its withdrawal. Am J Med . 1987; 82(Suppl 5A):20-6. [PubMed 3296749]

93. Schuckit MA. Alcohol and drug interactions with antianxiety medications. Am J Med . 1987; 82(Suppl 5A):27-33. [PubMed 2884873]

94. Gammans RE, Bullen WW, Briner L et al. The effects of buspirone binding to the binding of digoxin, dilantin, propranolol, and warfarin to human plasma. Fed Proc . 1985; 44:1123.

95. Goldberg HL. Buspirone—a new antianxiety agent not chemically related to any presently marketed drugs. Psychopharmacol Bull . 1979; 15:90-2. [PubMed 34846]

96. Bond AJ, Lader MH. Comparative effects of diazepam and buspirone on subjective feelings, psychological tests and the EEG. Int Pharmacopsychiatry . 1981; 16:212-20. [PubMed 6121766]

97. McKinney GR (Mead Johnson Pharmaceutical Division, Evansville, IN): Personal communication; 1987 June 19.

98. Murphy SM, Owen RT, Tyrer PJ. Withdrawal symptoms after six weeks' treatment with diazepam. Lancet . 1984; 2:1389. [PubMed 6150380]

99. Othmer E, Othmer SC. Effect of buspirone on sexual dysfunction in patients with generalized anxiety disorder. J Clin Psychiatry . 1987; 48:201-3. [PubMed 2883173]

100. Lucki I, Rickels K, Giesecke MA et al. Differential effects of the anxiolytic drugs, diazepam and buspirone, on memory function. Br J Clin Pharmacol . 1987; 23:207-11. [PubMed 2881573][PubMedCentral]

101. Spencer DG Jr, Traber J. The interceptive discriminative stimuli induced by the novel putative anxiolytic TVX Q 7821: behavioral evidence for the specific involvement of serotonin 5-HT1A receptors. Psychopharmacology . 1987; 91:25-9. [PubMed 2881318]

102. Peroutka SJ. Selective labeling of 5-HT1A and 5-HT1B binding sites in bovine brain. Brain Res . 1985; 344:167-71. [PubMed 4041865]

103. Smith LM, Peroutka SJ. Differential effects of 5-hydroxytryptamine1A selective drugs on the 5-HT behavioral syndrome. Pharmacol Biochem Behav . 1986; 24:1513-9. [PubMed 2942947]

104. Caccia S, Vigano GL, Mingardi G et al. Clinical pharmacokinetics of oral buspirone in patients with impaired renal function. Clin Pharmacokinet . 1988; 14:171-7. [PubMed 3370902]

105. Lader MH, Napoliello MJ. A study of buspirone co-prescribed with antihistamines in 68 anxious ambulatory patients. J Clin Psychopharmacol . 1988; 8:146-8. [PubMed 2897380]

106. Ross CA. Buspirone in the treatment of tardive dyskinesia. Med Hypotheses . 1987; 22:321-8. [PubMed 2884555]

107. Ross CA, Matas M. A clinical trial of buspirone and diazepam in the treatment of generalized anxiety disorder. Can J Psychiatry . 1987; 32:351-5. [PubMed 3308052]

108. Fontaine R, Beaudry P, Beauclair L et al. Comparison of withdrawal of buspirone and diazepam: a placebo controlled study. Prog Neuro-Psychopharmacol & Biol Psychiatry . 1987; 11:189-97.

109. Olajide D, Lader M. A comparison of buspirone, diazepam, and placebo in patients with chronic anxiety states. J Clin Psychopharmacol . 1987; 7:148-52. [PubMed 2885344]

110. Dalhoff K, Poulsen HE, Garred P et al. Buspirone pharmacokinetics in patients with cirrhosis. Br J Clin Pharmacol . 1987; 24:547-50. [PubMed 3689635][PubMedCentral]

111. Seppala T, Ranta T, Shrotriya RC. Serum prolactin levels after buspirone in man. Med Biol . 1987; 65:61-3. [PubMed 3613693]

112. Goa KL, Ward A. Buspirone: a preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs . 1986; 32:114-29. [PubMed 2874976]

113. Singh AN, Beer M. A dose range-finding study of buspirone in geriatric patients with symptoms of anxiety. J Clin Psychopharmacol . 1988; 8:67-8. [PubMed 3351003]

114. Feighner JP. Buspirone in the long-term treatment oi generalized anxiety disorder. J Clin Psychiatry . 1987; 48(Suppl):3-6. [PubMed 3320034]

115. Gammans RE, Mayol RF, Mackenthun AV et al. Relationship between dose and bioavailability of buspirone. Clin Res . 1983; 31:628A.

116. Mayol RF, Adamson DS, Gammans RE et al. Pharmacokinetics and disposition of14C-buspirone HCL after intravenous and oral dosing in man. Clin Pharmacol Ther . 1985; 37:210.

117. Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products. 5th ed. Baltimore: The Williams & Wilkins Co; 1984:I-10.

118. Molitor JA, Gammans RE, Carroll CM et al. Effect of buspirone on mixed function oxidase activity in rats. Fed Proc . 1985; 44:1257.

119. Gammans RE, Pfeffer M, Westrick ML et al. Lack of interaction between cimetidine and buspirone. Pharmacotherapy . 1987; 7:72-9. [PubMed 2888096]

120. Hansten PD, Horn JR. Buspirone and cimetidine. Drug Interact Newsl . 1987; 7:38.

121. APA Work Group to Revise DSM-III. Diagnostic and statistical manual of mental disorders: DSM-III-R. 3rd ed, rev. Washington, DC: American Psychiatric Association. 1987:235-53,392.

122. Anon. Buspirone—a radical advance in the treatment of anxiety? Lancet . 1988; 1:804-6. Editorial.

123. Mead Johnson Pharmaceuticals. BuSpar® (buspirone hydrochloride) information for the healthcare professional. Evansville, IN; 1986 Oct.

124. Lader M. Long-term anxiolytic therapy: the issue of drug withdrawal. J Clin Psychiatry . 1987; 48(Suppl):12-6. [PubMed 2891684]

125. Gammans RE, Mayol RF, Eison MS. Concentration of buspirone and 1-pyrimidinylpiperazine, a metabolite, in rat brain. Fed Proc . 1983; 42:377.

126. Caccia S, Garattini S, Mancinelli A et al. Identification and quantitation of 1-(2-pyrimidinyl)piperazine, an active metabolite of the anxiolytic agent buspirone, in rat plasma and brain. J Chromatogr . 1982; 252:310-4. [PubMed 7182413]

127. Caccia S, Fong MH, Guiso G. Disposition of the psychotropic drugs buspirone, MJ-13805 and piribedil, and of their common metabolite 1-(2-pyrimidinyl)-piperazine in the rat. Xenobiotica . 1985; 15:835-44. [PubMed 2866634]

128. Ereshefsky L. Buspirone's advantages over benzodiazepine anxiolytics. Clin Pharm . 1984; 3:654-5. [PubMed 6150783]

129. Hatfield SM, Parenti MA. Buspirone hydrochloride. Hosp Pharm . 1987; 22:580-92.

130. Fabre LF. Double-blind comparison of buspirone with diazepam in anxious patients. Curr Ther Res . 1987; 41:751-9.

131. Yevich JP, Temple DL Jr, New JS et al. Buspirone analogues: 1. Structure-activity relationships in a series of N-aryl-and heteroarylpiperazine derivatives. J Med Chem . 1983; 26:194-203. [PubMed 6131130]

132. New JS, Yevich JP, Eison MS et al. Buspirone analogues: 2. Structure-activity relationships of aromatic imide derivatives. J Med Chem . 1986; 29:1476-82. [PubMed 2874226]

133. Williams M. Anxioselective anxiolytics. J Med Chem . 1983; 26:619-28. [PubMed 6132997]

134. Trulson ME, Preussler DW, Howell GA et al. Raphe unit activity in freely moving cats: effects of benzodiazepines. Neuropharmacology . 1982; 21:1045-50. [PubMed 6292767]

135. Eison MS, VanderMaelen CP, Matheson GK et al. Interactions of the anxioselective agent buspirone with central serotonergic systems. Soc Neurosci Abstr . 1983; 9:435.

136. Van de Kar LD, Urban JH, Lorens SA et al. The non-benzodiazepine anxiolytic buspirone inhibits stess-induced renin secretion and lowers heart rate. Life Sci . 1985; 36:1149-55. [PubMed 2858796]

137. Offord SJ, Ordway GA, Frazer A. Application of [125I]iodocyanopindolol to measure 5-hydroxytryptamine1B receptors in the brain of the rat. J Pharmacol Exp Ther . 1988; 244:144-53. [PubMed 3335996]

138. Wilkinson LO, Abercrombie ED, Rasmussen K et al. Effect of buspirone on single unit activity in locus coeruleus and dorsal raphe nucleus in behaving cats. Eur J Pharmacol . 1987; 136:123-7. [PubMed 3595712]

139. Peroutka SJ, Mauk MD, Kocsis JD. Modulation of neuronal activity in the hippocampus by 5-hydroxytryptamine and 5-hydroxytryptamine1A selective drugs. Neuropharmacology . 1987; 26:139-46. [PubMed 2884586]

140. Trulson ME, Trulson TJ. Buspirone decreases the activity oi serotonin-containing neurons in the dorsal raphe in freely-moving cats. Neuropharmacology . 1986; 25:1263-6. [PubMed 2879255]

141. VanderMaelen CP, Matheson GK, Wilderman RC et al. Inhibition of serotonergic dorsal raphe neurons by systemic and iontophoretic administration of buspirone, a non-benzodiazepine anxiolytic drug. Eur J Pharmacol . 1986; 129:123-30. [PubMed 2876903]

142. Rowan MJ, Anwyl R. Neurophysiological effects of buspirone and isapirone in the hippocampus: comparison with 5-hydroxytryptamine. Eur J Pharmacol . 1987; 132:93-6.

143. Mansbach RS, Barrett JE. Discriminative stimulus properties of buspirone in the pigeon. J Pharmacol Exp Ther . 1987; 240:364-9. [PubMed 3806400]

144. Gardner CR. Recent developments in 5HT-related pharmacology of animal models of anxiety. Pharmacol Biochem Behav . 1986; 24:1479-85. [PubMed 2873594]

145. Davis M, Cassella JV, Kehne JH. Serotonin does not mediate anxiolytic effects of buspirone in the fear-potentiated paradigm: comparison with 8-OH-DPAT and ipsapirone. Psychopharmacology (Berl) . 1988; 94:14-20. [PubMed 2894698]

146. Pellow S, Johnston AL, File SE. Selective agonists and antagonists for 5-hydroxytryptamine receptor subtypes, and interactions with yohimbine and FG 7142 using the elevated plus-maze test in the rat. J Pharm Pharmacol . 1987; 39:917-28. [PubMed 2892916]

147. Kennett GA, Marcou M, Dourish CT et al. Single administration of 5-HT agonists decreases 5-HT1A presynaptic, but not receptor-mediated responses: relationship to antidepressant-like action. Eur J Pharmacol . 1987; 138:53-60. [PubMed 2442002]

148. Kennett GA, Dourish CT, Curzon G. Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. Eur J Pharmacol . 1987; 134:265-74. [PubMed 2883013]

149. Mennini T, Gobbi M, Ponzio F et al. Neurochemical effects of buspirone in rat hippocampus: evidence for selective activation of 5HT neurons. Arch Int Pharmacodyn Ther . 1986; 279:40-9. [PubMed 2421657]

150. Witkin JM, Mansbach RS, Barrett JE et al. Behavioral studies with anxiolytic drugs: IV. Serotonergic involvement in the effects of buspirone on punished behavior of pigeons. J Pharmacol Exp Ther . 1987; 243:970-7. [PubMed 2891840]

151. Peroutka SJ, Huang S, Allen GS. Canine basilar artery contractions mediated by 5-hydroxytryptamine1A receptors. J Pharmacol Exp Ther . 1986; 237:901-6. [PubMed 2940360]

152. Zisook S. Buspirone hydrochloride: a unique new anxiolytic agent. Pharmacokinetics, clinical pharmacology, abuse potential and clinical efficacy. Commentary 1. Pharmacotherapy . 1984; 4:321-2.

153. Ereshefsky L. Buspirone hydrochloride: a unique new anxiolytic agent. Pharmacokinetics, clinical pharmacology, abuse potential and clinical efficacy. Commentary 2. Pharmacotherapy . 1984; 4:322.

154. Lydiard RB. Buspirone hydrochloride: a unique new anxiolytic agent. Pharmacokinetics, clinical pharmacology, abuse potential and clinical efficacy. Commentary 3. Pharmacotherapy . 1984; 4:322-3.

155. Wells BG. Buspirone hydrochloride: a unique new anxiolytic agent. Pharmacokinetics, clinical pharmacology, abuse potential and clinical efficacy. Commentary 4. Pharmacotherapy . 1984; 4:323-4.

156. Morton WA Jr. Buspirone hydrochloride: a unique new anxiolytic agent. Pharmacokinetics, clinical pharmacology, abuse potential and clinical efficacy. Commentary 5. Pharmacotherapy . 1984; 4:324.

157. Schatzberg AF. Buspirone hydrochloride: a unique new anxiolytic agent. Pharmacokinetics, clinical pharmacology, abuse potential and clinical efficacy. Commentary 6. Pharmacotherapy . 1984; 4:324.

158. Beaumont G. Buspirone: its potential role in the treatment of general practice anxiety. Br J Clin Pract . 1985; 38(Symp Suppl):100-6.

159. Perry PJ. Assessment of addiction liability of benzodiazepines and buspirone. Drug Intell Clin Pharm . 1985; 19:657-9. [PubMed 2864227]

160. Tyrer P, Owen R. Anxiety in primary care: is short-term drug treatment appropriate? J Psychiatr Res . 1984; 18:73-8.

161. McMillen BA, Scott SM, Williams HL et al. Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. Naunyn-Schmiedebergs Arch Pharmacol . 1987; 335:454-64. [PubMed 2439924]

162. Pellow S, File SE. Is tofisopam an atypical anxiolytic? Neurosci Biobehav Rev . 1986; 10:221-7.

163. Skolnick P, Paul SM, Weissman BA. Preclinical pharmacology of buspirone hydrochloride. Pharmacotherapy . 1984; 4:308-14. [PubMed 6151169]

164. McMillen BA, McDonald CC. Selective effects of buspirone and molindone on dopamine metabolism and function in the striatum and frontal cortex of the rat. Neuropharmacology . 1983; 22:273-8. [PubMed 6133232]

165. Hoehn-Saric R. Neurotransmitters in anxiety. Arch Gen Psychiatry . 1982; 39:735-42. [PubMed 6124225]

166. Allen LE, Ferguson HC, Cox RH Jr. Pharmacologic effects of MJ 9022-1, a potential tranquilizing agent. Arzneimittelforschung . 1974; 24:917-22. [PubMed 4212236]

167. Dommisse CS, DeVane CL. Buspirone: a new type of anxiolytic. Drug Intell Clin Pharm . 1985; 19:624-8. [PubMed 2864225]

168. Rickels K. Antianxiety therapy: potential value of long-term treatment. J Clin Psychiatry . 1987; 48(Suppl):7-11. [PubMed 2891688]

169. Liegghio NE, Yeragani VK, Moore NC. Buspirone-induced jitteriness in three patients with panic disorder and one patient with generalized anxiety disorder. J Clin Psychiatry . 1988; 49:165-6. [PubMed 3356675]

170. Sills MA, Wolfe BB, Frazer A. Determination of selective and nonselective compounds for the 5-HT1A and 5-HT1B receptor subtypes in rat frontal cortex. J Pharmacol Exp Ther . 1984; 231:480-7. [PubMed 6502510]

171. Lerman JA, Kaitin KI, Dement WC et al. The effects of buspirone on sleep in the rat. Neurosci Lett . 1986; 72:64-8. [PubMed 2880319]

172. Wander TJ, Nelson A, Okazaki H et al. Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro. Eur J Pharmacol . 1986; 132:115-21. [PubMed 3816971]

173. Louilot A, Le Moal M, Simon H. A study of the effects of buspirone, BMY 13805, and 1-PP on dopaminergic metabolism in the nucleus accumbens using in vivo voltammetry in freely moving rats. Life Sci . 1986; 39:685-92. [PubMed 2874469]

174. Hanson RC, Braselton JP, Hayes DC et al. Cardiovascular and renal effects of buspirone in several animal models. Gen Pharmacol . 1986; 17:267-74. [PubMed 2873078]

175. Liegghio NE, Yeragani VK. Buspirone-induced hypomania: a case report. J Clin Psychopharmacol . 1988; 8:226-7. [PubMed 3379150]

176. Shimizu H, Hirose A, Tatsuno T et al. Pharmacological properties of SM-3997: a new anxioselective anxiolytic candidate. Jpn J Pharmacol . 1987; 45:493-500. [PubMed 2895201]

177. Witkin JM Barrett JE. Interaction of buspirone and dopaminergic agents on punished behavior of pigeons. Pharmacol Biochem Behav . 1986; 24:751-6. [PubMed 2871566]

178. Sanghera MK, German DC. The effects of benzodiazepine and non-benzodiazepine anxiolytics on locus coeruleus unit activity. J Neural Transm . 1983; 57:267-79. [PubMed 6140300]

179. Saller CF, Salama AI. 3-Methoxytyramine accumulation: effects of typical neuroleptics and various atypical compounds. Naunyn-Schmiedebergs Arch Pharmacol . 1986; 334:125-32. [PubMed 2878374]

180. Louilot A, Le Moal M, Simon H. Presynaptic control of dopamine metabolism in the nucleus accumbens: lack of effect of buspirone as demonstrated using in vivo voltammetry. Life Sci . 1987; 40:2017-24. [PubMed 3573992]

181. Ortiz A, Pohl R, Gershon S. Azaspirodecanediones in generalized anxiety disorder: buspirone. J Affect Disord . 1987; 13:131-43. [PubMed 2960708]

182. Rimele TJ, Henry DE, Lee DKH et al. Tissue-dependent alpha adrenoceptor activity of buspirone and related compounds. J Pharmacol Exp Ther . 1987; 241:771-8. [PubMed 3037069]

183. Bianchi G, Garattini S. Blockade of α2-adrenoceptors by 1-(2-pyrimidinyl)-piperazine (PmP) in vivo and its relation to the activity of buspirone. Eur J Pharmacol . 1988; 147:343-50. [PubMed 2897918]

184. Rickels K, Schweizer E, Csanalosi I et al. Long-term treatment of anxiety and risk of withdrawal: prospective comparison of clorazepate and buspirone. Arch Gen Psychiatry . 1988; 45:444-50. [PubMed 2895993]

185. Evens RP (Mead Johnson Pharmaceuticals, Evansville, IN): Personal communication; 1988 July 20.

186. Reviewers' comments (personal observations); 1988 July.

187. McMillen BA, DaVanzo EA, Scott SM et al. N-alkyl-substituted aryl-piperazine drugs: relationship between affinity for serotonin receptors and inhibition of aggression. Drug Dev Res . 1988; 12:53-62.

188. Rapoport DM, Greenberg HE, Goldring RM. A placebo controlled comparison of the effects of buspirone and diazepam on control of breathing. (unpublished observations)

189. McGowan G, Napoliello M, Alms D. Buspirone for the management of anxiety in patients with concomitant medical conditions: a retrospective preliminary evaluation. Curr Ther Res . 1988; 43:481-6.

190. Andrade R, Nicoll RA. Novel anxiolytics discriminate between postsynaptic serotonin receptors mediating different physiologic responses on single neurons of the rat hippocampus. Naunyn-Scmiedebergs Arch Pharmacol . 1987; 336:5-10.

191. Rakel R, Alms D, Boehm C et al. The safety of long-term buspirone in treatment of chronic anxiety—a multicenter international study. (unpublished observations)

192. Robinson DS, Roberts DL, Shrotriya RC et al. Non-benzodiazepine anxiolytics, including buspirone. Paper presented at NCDEU annual meeting. Key Biscayne, FL: 1988 May 31-June 3.

193. Robinson D, Napoliello MJ, Schenck J. A final report of the safety of buspirone as an anxiolytic drug in elderly versus young patients. (unpublished observations)

194. Levine S, Napoliello MJ. A study of buspirone coprescribed with histamine H2-receptor antagonists in anxious patients. Int Clin Psychopharmacol . 1988; 3:83-6. [PubMed 3356893]

195. Ritchie EC, Bridenbaugh RH, Jabbari B. Acute generalized myoclonus following buspirone administration. J Clin Psychiatry . 1988; 49:242-3. [PubMed 3379031]

196. Parke-Davis. Nardil® (phenelzine sulfate) prescribing information. In: Huff BB, ed. Physicians' desk reference. 43rd ed. Oradell, NJ: Medical Economics Company Inc; 1989:1571-2.

197. Smith Kline & French Laboratories. Parnate® (tranylcypromine sulfate) prescribing information. In: Huff BB, ed. Physicians' desk reference. 42nd ed. Oradell, NJ: Medical Economics Company Inc; 1988(Suppl A):A47-9.

198. Bodkin JA, Teicher MH. Fluoxetine may antagonize the anxiolytic action of buspirone. J Clin Psychopharmacol . 1989; 9:150. [PubMed 2786010]

199. Alessi N, Bos T. Buspirone augmentation of fluoxetine in a depressed child with obsessive-compulsive disorder. Am J Psychiatry . 1991; 148:1605-6. [PubMed 1928487]

200. Markovitz PJ, Stagno SJ, Calabrese JR. Buspirone augmentation of fluoxetine in obsessive-compulsive disorder. Am J Psychiatry . 1990; 147:790-800.

201. Sporer KA. The serotonin syndrome. Implicated drugs, pathophysiology and management. Drug Saf . 1995; 13:94-104. [PubMed 7576268]

202. Beasley CM, Masica DN, Heiligenstein JH et al. Possible monoamine oxidase inhibitor-serotonin uptake inhibitor interaction: fluoxetine clinical data and preclinical findings. J Clin Psychopharmacol . 1993; 13:312-20. [PubMed 8227489]

203. Bristol-Myers Squibb, Princeton, NJ: Personal communication.

204. Mahmood I, Sahajwalla C. Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet . 1999; 36:277-87. [PubMed 10320950]

205. Barbhaiya RH, Shukla UA, Pfeffer M et al. Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses. Eur J Clin Pharmacol . 1994; 46:41-7. [PubMed 7911763]

206. Lamberg TS, Kivistö KT, Neuvonen PJ. Concentrations and effects of buspirone are considerably reduced by rifampicin. Br J Clin Pharmacol . 1998; 45:381-5. [PubMed 9578186][PubMedCentral]