Buspirone: 5-HT1A azapirone anxiolytic

Buspirone is the international name for the anxiolytic from the azapirone class. In Germany the substance is available as a generic and under the brand name Bespar; internationally it is known as Buspirone (BuSpar in the United States until withdrawal). The German spelling Buspiron and the English spelling Buspirone refer to the same active ingredient with identical pharmacology.

Unlike benzodiazepines and z-drugs, buspirone does not act on the GABA receptor but as a partial agonist at the 5-HT1A receptor and a weak dopamine D2 antagonist. The result is a favourable safety profile without sedation, respiratory depression, tolerance or addiction potential. The onset of action requires one to four weeks, however, which means buspirone is not suitable for acute symptom relief.

Mechanism of action

Buspirone is a partial agonist at the presynaptic 5-HT1A autoreceptor and at the postsynaptic 5-HT1A heteroreceptor. Initial stimulation of presynaptic autoreceptors dampens serotonin release. Over weeks of therapy these autoreceptors desensitise, which normalises serotonergic neurotransmission in the prefrontal cortex and limbic system.

Buspirone also blocks dopamine D2 receptors with moderate affinity. The active main metabolite 1-pyrimidinylpiperazine (1-PP) has noradrenergic properties and contributes to the clinical effect.

Because buspirone is neither GABAergic nor glutamatergic, it lacks typical benzodiazepine features: no sedating, muscle-relaxant or anticonvulsant action, no respiratory depression in overdose, no tolerance over time and no physical dependence potential.

Indications

• Generalised anxiety disorder (GAD): classic indication, often the agent of choice in patients with substance use history or chronic course
• Anxiety disorders with anxious-tense component: particularly when sedation is undesirable
• Off-label uses: augmentation of SSRI therapy, sexual dysfunction under SSRI, tic disorders, alcohol-withdrawal-related anxiety

Compared with benzodiazepines, buspirone is less effective in panic disorder and not approved for this. Acute stress reaction or short-term sedation are also unsuitable indications because the onset is too slow.

Dosing and administration

Starting dose: 5 mg three times daily or 7.5 mg twice daily. Titration: increase by 5 mg every two to three days up to clinical effect.

Maintenance dose: usually 15 to 30 mg per day in two or three divided doses. Maximum dose: 60 mg per day.

Take consistently either always on an empty stomach or always with food, since meals alter bioavailability. Important: no grapefruit juice, since it can double or triple plasma levels via CYP3A4 inhibition.

Patients should know that buspirone does not work within minutes or hours. The first noticeable effects appear after 7 to 14 days, the full effect after 4 to 6 weeks. Anyone expecting an immediate calming pill will be disappointed.

Side effects

Common (above 1 %): dizziness, headache, nausea, nervousness, insomnia, drowsiness, fatigue, dry mouth, mild gastrointestinal complaints.

Uncommon: tachycardia, palpitations, chest pain, tinnitus, visual disturbance, tremor, paraesthesia, sweating, rash.

Rare: serotonin syndrome (especially with MAO inhibitors or serotonergic substances), extrapyramidal symptoms, hyperprolactinaemia, allergic reactions, depressive symptoms.

Important points for patients:

• Dizziness and drowsiness usually appear in the first days and improve
• Buspirone does not cause dependence and has no withdrawal syndrome
• Overdose is much less dangerous than with benzodiazepines, life-threatening courses are rare
• Package leaflets often warn about driving; impairment is mild compared with benzodiazepines

Interactions

• Strong CYP3A4 inhibitors (itraconazole, erythromycin, diltiazem, verapamil, HIV protease inhibitors, grapefruit juice): markedly raised buspirone levels; reduce dose or avoid combination
• Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St John's wort): reduced efficacy; increase dose or choose alternative anxiolytic
• MAO inhibitors (tranylcypromine, moclobemide): risk of hypertensive crisis and serotonin syndrome, combination contraindicated
• SSRIs, SNRIs, triptans: increased risk of serotonin syndrome, usually clinically tolerable; counsel on warning signs
• Trazodone: possible rise in liver transaminases
• Alcohol: additive impairment of attention and reaction; best avoided
• Haloperidol: buspirone may raise haloperidol levels

Special considerations

Pregnancy: data are limited. If clinically necessary, use cautiously in the first trimester; in the second and third trimesters under careful benefit-risk evaluation.

Breastfeeding: not adequately studied, use with caution.

Children and adolescents: not approved in Germany; off-label use is possible but a specialist decision.

Older patients: buspirone is favourable compared with benzodiazepines because of the absence of fall risk from sedation. Caution is advised in hepatic or renal impairment.

Hepatic impairment: contraindicated in severe hepatic impairment due to marked level rises. Renal impairment: contraindicated in severe renal impairment.

Combination with psychotherapy: in generalised anxiety disorder, the combination of pharmacotherapy and psychotherapy (cognitive behavioural therapy) yields the most durable results.

Related substances

• Paroxetin as an SSRI for anxiety disorders
• Pregabalin, alternative for generalised anxiety disorder
• Agomelatin, melatoninergic antidepressant with anxiolytic properties
• Sertralin, widely used SSRI

Frequently asked questions

Sources

• BfArM Federal Institute for Drugs and Medical Devices
• AWMF guideline anxiety disorders
• Gelbe Liste buspirone monograph
• EMA European Medicines Agency