Anxiolytics

Anxiolytics
PGY 4110/3320
Introduction
• Anxiety is both a normal emotion and a disorder which can cause
profound distress and functional impairment.
• The range of treatments available for anxiety has improved
substantially in the last 20 years.
• This has in part been due to improved understanding of the neurobiological
mechanisms underlying anxiety.
• Selective serotonin reuptake inhibitors (SSRIs) are now considered
first-line pharmacological therapy for all the anxiety disorders except
simple phobia.
• SSRIs may cause anxiety to increase during initial therapy before the
anxiolytic effect emerges.
• Other antidepressants shown to be effective in anxiety disorders
include:
• Mirtazapine, venlafaxine and, although less commonly used, tricyclic
antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).
• Benzodiazepines were used widely in the past for anxiety, but
concerns over dependence and withdrawal effects have now greatly
limited their use.
• However, they continue to have a role in those non-responsive to other agents
and for short-term use during antidepressant initiation.
• Several anticonvulsant medications may also be useful in anxiety
(e.g. pregabalin)
• Some atypical antipsychotics also have a limited evidence base to
support their use in treatment-resistant anxiety disorders.
• Psychotherapy has an important role to play in the treatment of anxiety
disorders.
GENERALIZED ANXIETY DISORDER
(GAD)
A. Excessive anxiety and worry lasting for at least 6 months and
difficulty controlling the worry
B. Presence of at least 3 of the following symptoms:
• Feeling keyed up or on edge; restlessness
• Becoming easily fatigued
• Mind going blank; difficulty concentrating
• Irritability
• Muscle tension
• Sleep disturbance, usually insomnia
Pathophysiology
Noradrenergic model
A. Autonomic nervous system of anxious patients is hypersensitive and

overreacts to stimuli
B. In humans, states of fear and anxiety are associated with an increase
in norepinephrine (NE) release.
• The major site of NE cell bodies in the brain is the locus coeruleus (LC).
C. In response to fear, the LC serves as the alarm center to activate NE
release and stimulates the sympathetic and parasympathetic nervous
systems.
D. In response to stress, corticotropin -releasing factor (CRF) is
released from the median eminence of the hypothalamus, where it
subsequently binds to receptors at the anterior pituitary and increases
adrenocorticotropic hormone (ACTH) release into the bloodstream.
• ACTH consequently acts at the adrenal cortex to facilitate release of
glucocorticoids such as cortisol.
• This system, known as the hypothalamic-pituitary-adrenal (HPA) axis, is
an important component of the response to stress and is dysregulated in
anxiety.
• Central administration of CRF in animals results in increases in behavior
indicative of anxiety.
E. Chronic central noradrenergic overactivity downregulates α-2
adrenoreceptors in patients with GAD.
F. Drugs with anxiolytic effects (e.g., lorazepam, escitalopram,
venlafaxine) inhibit LC firing, decrease NE activity, and block the
effects of anxiogenic drugs
Gamma-Amino Butyric Acid (GABA)
Receptor Model
A. GABA is the major inhibitory neurotransmitter in the central
nervous system (CNS)
B. Drugs that reduce anxiety and produce sedation target GABA A
receptors
C. GABAB receptor is a G-protein coupled receptor thought to be
involved in the presynaptic inhibition of GABA release
D. GABA has a strong regulatory or inhibitory effect on the serotonin
(5-HT), NE, and dopamine (DA) systems
Serotonin Model
• There is conflicting evidence about whether 5-HT is increased or
decreased in anxiety
• But it is now thought that there are two different pathways from the
raphe:
• Medial raphe nucleus (MRN)-Thought to modulate fear and anticipatory
anxiety.
• Dorsal raphe nucleus (DRN)- Is thought to modulate cognitive processes
associated with anxiety.
• It is postulated that an excess of 5-HT may be anxiogenic in one
pathway and anxiolytic in the other, perhaps through actions at
different 5-HT-receptors
• Abnormalities in serotonergic functioning occur through release and
uptake at:
• The presynaptic autoreceptors (5-HT1A/1D)
• The serotonin reuptake transporter site, or
• At the postsynaptic receptors (5-HT,1A, 5-HT2A, and 5-HT2c)
Neuroimaging Studies
A. Frontal and occipital brain areas are integral to anxiety response
B. Increase in cortical activity and decrease in basal ganglia activity
occur in GAD.
Treatment guidelines
A. Initial therapy of GAD can consist of medications, psychotherapy, or
the combination. Both approaches are efficacious, but it is unclear if
combination therapy confers greater overall efficacy.
B. First-line pharmacotherapy is with SSRI’s or SNRI’s
C. If full symptoms persist after an adequate trial of a first-line
medication, treatment guidelines recommend switching to another
SSRI or SNRI.
As an alternative, augmentation with a second generation antipsychotic (SGA),
benzodiazepine (BZD),antihistamine, Buspirone, or pregabalin may be
appropriate depending on comorbid symptoms.
D. With current data, it is not clear whether it is better to increase the
dose, augment, or switch when there has been a partial response to drug
therapy.
E. Response to treatment after a trial period is described as remitted,
improved, partial response, or non response after 4-6 weeks.
F. If at least partial response has occurred after 4-6 weeks of an
adequate trial, pharmacotherapy should be titrated to a maximal
tolerated dose and response reevaluated at 12 weeks
Level of Intervention British Association for Psychopharmacology Guidelines
First-Line SSRI’s:Ecscitalopram, paroxetine, sertraline.
SNRI’s:Venlafaxine
BZD: Alprazolam, Diazepam
TCA: Imipramine
Buspirone
Hydroxyzine
Second-Line Switch to another evidence-based treatment after non-response to initial treatment
Third-Line Consider use of BZD after non-response: to SSRI and SNRI treatment.
Consider combination of CBT with Pharmacotherapy
Selective Serotonin Reuptake Inhibitors
Dosing Recommendations
• All SSRI’s can be dosed once daily
• Pediatric: Starting dose is one-half of depression dose; studies used fluoxetine I 0
mg/day and sertraline 25 mg/day.
• Children and adolescents may require twice daily dosing with sertraline and
fluvoxamine because of short half-lives.
• Medication should be slowly tapered over several months when discontinued
• Elderly :
a. Antidepressants should be started at very low doses and titrated
i. Citalopram 5-10 mg/day (maximum daily dose = 20 mg/day)
ii. Sertraline 12.5-25 mg/day (dosage range 50-100 mg/day)
Serotonin Norepinephrine Reuptake
Inhibitors
Dosing
Venlafaxine
• Pediatric - Clinical trial used a starting dose of venlafaxine XR 37.5
mg/day and titrated upward according to body weight.
• The maximum dose used was 225 mg/day for participants weighing 50 kg or
more.
• Elderly - Venlafaxine XR starting dose is 37.5 mg/day (dosage range
75·225 mg/day)
Duloxetine
• Pediatric - For children 7 to 17 years, the duloxetine starting dose is 30
mg/day for two weeks.
• The dose can be increased in 30 mg increments up to a maximum dose of 120
mg/day.
• Elderly - Duloxetine starting dose is 30 mg/day for two weeks before
increasing to 60 mg/day. Use should be avoided if CrCl is less than
30ml/min.
Onset of Action
• The response time for an antidepressant in GAD is generally 4-12
weeks
• Initial pharmacotherapy with an SSRI will not lead to remission for
many patients with GAD; approximately 61% to 67% of patients will
not achieve remission.
Buspirone
• Mechanism of Action - Believed to exert anxiolysis through 5-HT 1A
partial agonist activity at the presynaptic 5-HT receptors; has moderate
affinity for brain D2 receptors.
• Dosing Recommendations- Starting dose is 7.5 mg twice daily,
dosage range is 15-60 mg/day, titrate in increments of 5 mg/day every
2-3 days to effective dose.
• Full therapeutic benefit may not be evident for 4-6 weeks
Patient Education
1. Onset of action is delayed by at least 2-4 weeks
2. Medication must be taken 2-3 times per day and consistently taken
with or without food so the amount of drug absorbed will be the same
3. Anticipated duration of therapy is one year after response
4. Avoid ingestion with alcohol because of possible increased CNS
effects
5. Buspirone as monotherapy does not treat underlying depression
symptoms, if present
Hydroxyzine
Mechanism of Action- Histamine (H1) receptor antagonist and
serotonin (5-HT2) receptor antagonist
Onset of Action - The sedative effects of hydroxyzine are typically seen
within 30 minutes
-END-

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A. Autonomic nervous system of anxious patients is hypersensitive and

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