Chapter 14

Buspirone

Introduction

• Partial agonist of the 5-HT1A receptor• There is high regional density of 5-HT1A

receptors in midbrain, hippocampus, and limbic region.

• Consistent with the notion that 5-HT neurotransmission modulates mood and anxiety.

• Therefore, drugs targeting this receptor hold interest for the treatment of mood disorders.

History

• Buspirone was synthesized in 1968 in Mead Johnson’s lab.

• Originally studied as antipsychotic, but failed clinically.

• However, it had a marked taming effect in aggressive monkeys.

• Anti-anxiety agent.

Pharmacological Profile

• Inactive in receptor binding at noradrenergic, cholinergic and histaminergic sites.

• Dopmine receptor binding is believed to play no role in therapeutic or side effects.

• The antianxiety properties of buspirone appear to be its actions at both pre- and postsynaptic 5-HT1A receptors.

Pharmacokinetics and Mechanism of Action

• Oral administration• Half-life of 3-4 hours

– prolonged by food ingestion and hepatic/renal impairment

• Metabolites– 5-OH-Bu, 8-OH-Bu, 1-PP(1-2-pyrimidinyl piperazine),

6-OH-Bu• 1-PP has noradrenergic effects• 6-OH-Bu

– High affinity & partial agonist activity for the 5-HT1A R– Contributes significantly to the therapeutic effect of bu

spirone• Buspirone increases plasma cortisol, prolaction

and growth hormone.

Buspirone VS benzodiazepine

• Does not impair psychomotor performance

• Lacks abuse potential

• Shows anti-depressant like activity

• Non-sedating

• Spares cognitive and memory functions

• But slow in action

• But has serotonin syndrome

• Somatic anxiety and psychic anxiety• Ongoing treatment found similar therapeutic res

ponse.• Stopping abruptly after 6 months revealed

– BZDs: Relapsed in 4 weeks (withdrawal syndrome)– Buspirone: No symptom changes

• Longterm follow up at 40 months after 6 months medication (Rickels and Schweizer 1990)– BZDs: 50% of patients still required BZDs– Buspirone: None required anxiolytics

Indications and Efficacy

• FDA: Generalized Anxiety Disorder– Initial15-20mg/day– Maximum60mg/day

• Nonapproved Clinical Indications– PTSD – Other anxiety disorders – Smoking cessation – Depression, adjunctive therapy usually with SSRIs an

d SNRIs– May required higher dosage for MDD treatment (90m

g/day)

Side Effects and Toxicology

• Dizziness(12%)• Drowsiness(10%)• Nausea(8%)• Headache(6%)• Nervousness(5%)• Fatigue(4%)• Insomnia,light-headedness,dry mouth(3%)• Excitement(2%)• No death yet. Unusually safe, except for potentia

l serotonin syndrome.

Conclusion

• Partial agonist of the 5-HT1A receptor.

• Indication: GAD (start with 15-20mg/day, maximum 30mg/day).

• Better than BZDs because of no dependence or withdrawal effects.

• However, no sedation and slower onset.