Chapter 14 Buspirone & Chapter 38 Treatment of Anxiety Disorders
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Transcript of Chapter 14 Buspirone & Chapter 38 Treatment of Anxiety Disorders
Chapter 14
Buspirone
9392G131BuspironeOral tablet30mg/drug/buspibuspirone/odetail9392G131430null9392G131BuspironeOral tablet15mg/drug/buspibuspirone/odetail9392G13158null
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.
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.