Chapter 14

Buspirone

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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 buspir

one 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

response. 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 a

nd SNRIs May required higher dosage for MDD treatment (90

mg/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 poten

tial serotonin syndrome.

Conclusion

Partial agonist of the 5-HT1A receptor. Indication: GAD (start with 15-20mg/da

y, maximum 30mg/day). Better than BZDs because of no depen

dence or withdrawal effects. However, no sedation and slower onset.

Chapter 38

Treatment of Anxiety Disorders

Introduction

Obsessive-Compulsive Disorder Panic Disorder Social Phobia Specific Phobia Generalized Anxiety Disorder Posttraumatic Stress Disorder Acute Stress Disorder and the

Immediate Aftermath of Trauma

Obsessive-Compulsive Disorder Lifetime prevalence rate: 1.6% 10th leading cause of disability worldwide 1st line: SSRIs (FDA fluvoxamine, fluoxetine, sertra

line, paroxetine) 2nd line: Clomipramine (due to its side effects) Augmentation/Combination:

Fluvoxamine + clomipramine IV clomipramine clomipramine + clonazepam OR antipsychotics (haloperidol & risperidon

e > olanzapine & quetiapine) Neurosurgical approaches (cingulotomy or anterior capsulotomy) Cognitive-behavioral therapy Deep brain stimulation/rTMS

Panic Disorder

1st line: SSRIs (FDA fluoxetine, sertraline, paroxetine), BZDs (FDA clonazepam) Somatic anxiety such as palpitations, sweating, tremor Sedation (be careful in elderly), abuse potential, withdrawal sym

ptoms Others:

TCAs (clomipramine) MAOIs SNRIs (FDAVenlafaxine XR) NaSSA (mirtazepine has possible benefit, but has been associate

d with the induction of panic attacks) NRIs (Reboxetine)

Maintenance treatment is recommended for 1-2 years Discontinuation symptoms

Social Phobia

Generalized social phobia 1st line: SSRIs (FDA paroxetine, sertraline, fluvoxamine) 2nd line: (venlafaxine FDA approved), BZDs, nefazodone,

mirtazapine, MAOIs (moclobemide received license in some countries)

Nongeneralized social phobia 1st line: B-blockers, BZDs

Others: CBT is efficacious. Anticonvulsants: gabapentine & pregabalin, they are well t

olerated, safe, less discontinuation symptoms Antipsychotics: may deserve further investigation Bupropion and TCAs are disappointing.

Duration of treatment: recommend for years

Specific Phobia

Lifetime prevalence: 8-12.5% No drug has been yet approved by FDA Serotonergic drugs seem logical choices

Paroxetine & escitalopram: some evidence Imipramine: no evidence Clonazepam: helpful in acute treatment of the so

matic anxiety that accompanies specific phobia Novel approach: D-cycloserine (NMDA receptor p

artial agonist) + psychotherapy (exposure-based CBT

Generalized Anxiety Disorder (1) Lifetime prevalence: 5-6% Anxiolytics: BZDs, buspirone TCAs: Imipramine (psychic anxiety) VS alproz

olam (somatic anxiety) SSRIs: Paroxetine, Escitalopram, Sertraline SNRIs: Venlafaxine, duloxetine

Psychic anxiety, long term efficacy, GAD with comorbid depression

Be careful of sexual dysfunction, hypertension

Generalized Anxiety Disorder (2)

Hydroxyzine, anticonvulsants (pregabalinapproved in europe), antipsychotics (quetiapine > ziprasidone, flupenthixol, sulpiride): with some evidence

Others: riluzole, agomelatine, CBT Mirtazapine and bupropion: less favore

d

Posttraumatic Stress Disorder

1st line: SSRI (FDAParoxetine, Sertraline) & Fluoxetine

SNRI: venlafaxine - some evidence Other Antidepressants: Nefazodone, Mi

rtazapine, TCA - insufficient evidence Antipsychotics : Adjunctive use for PTS

D symptoms resistant to SSRIs/SNRIs Alpha blocker: Prazosin – adjunctive us

e for sleep problem

Acute Stress Disorder and the Immediate Aftermath of Trauma

Risperidone: possible benefit in flashback symptoms

Hydrocortisone: greater benefit for subjects Recovering from high risk septic shock, cardiac surgery, AR

DS Who have illness-related corticosteroid insufficiency

CBT: shortened forms appear to be effective Imipramine: reduction in intrusion and hyperarousa

l symptoms (Robert et al. 1999), but failed in subsequent trials

Propranolol: no benefit (Stein et al. 2007) Temazepam: no benefit & possibly worse

Conclusion

SSRIs considered first-line drugs for most of the anxiety disorder categories.

Followed closely by SNRIs. They may offer some protection agains

t relapse. Consider side effects. Consider combination.

Thank you