This document discusses the treatment of anxiety disorders. It notes that antidepressant drugs take 3-4 weeks to have an effect, while benzodiazepines have a rapid onset of 30 minutes to 1 hour. It then lists and describes several common anxiety disorders - panic disorder, OCD, social anxiety disorder, PTSD, and GAD. It also discusses neurotransmitters implicated in anxiety like GABA, norepinephrine, and serotonin. Finally, it provides details on pharmacologic and non-pharmacologic treatment options for each anxiety disorder.

1. Treatment of Anxiety Disorders
time to onset of effects
 Antidepressant drugs are used to
treat anxiety disorders. These drugs
have a latency to onset of clinically
meaningful effects, typically 3 to 4
weeks or longer
 Benzodiazepines have a rapid onset
of effect (30 minutes to one hour)

2. Anxiety Disorders
 Panic Disorder (PD)
 Obsessive Compulsive Disorder (OCD)
 Social Anxiety Disorder (Social Phobia)
 Post-traumatic Stress Disorder (PTSD)
 Generalized Anxiety Disorder (GAD)
 Specific Phobia (Simple Phobia)

3. Neurotransmitters Implicated in
Anxiety
 Gamma-amino butyric acid (GABA)
 GABA-benzodiazepine receptor complex
 Norepinephrine (NE)
 Brainstem locus coeruleus
 Serotonin (5-hydroxytryptamine, 5-HT)

4. Anxiolytic Drugs
 Discovery
 meprobamate (1954)
 chlordiazepoxide (1957)
 First of many benzodiazepines

5. Panic Disorder
 With and without agoraphobia
 Panic attacks (unexpected)
 Anticipatory anxiety
 Generalized anxiety
 Avoidance (agoraphobia)
 Somatic symptoms

6. Pharmacologic Treatment of Panic
Disorder
 Antidepressants (latency to onset of effects)
 TCAs - imipramine, clomipramine
 MAOIs
 SSRI/SNRI - first choice for many patients
 Benzodiazepines (rapid onset of effects)
 First choice if rapid effect needed
 alprazolam (Xanax®)
 clonazepam (Klonopin®)
 Combinations

7. Adverse Effects
 SSRI/SNRI
 Activation - may cause initial jitteriness
 Gradual dose escalation recommended
 Sexual dysfunction
 Gastrointestinal side effects
 Withdrawal syndrome
 Benzodiazepines
 Sedation
 Potentiation of alcohol, other CNS depressants
 Dependence
 Psychomotor impairment, Ataxia
 Amnesia
 Withdrawal syndrome

8. Non-pharmacologic Treatment of Panic
Disorder
 Cognitive Behavioral Therapy (CBT)
 Frequently, pharmacologic treatment and CBT
are used in combination

9. Obsessive Compulsive Disorder
Common Obsessions Common Compulsions
 Contamination  Checking
 Aggression  Cleaning/washing
 Religious  Counting/Mental rituals
 Safety/harm  Repeating
 Need for symmetry  Ordering/arranging
 Somatic fears  Hoarding

10. Treatment of OCD
 Drugs that increase synaptic serotonin

11. Treatment of OCD
serotonin reuptake inhibitors (SRIs)
 clomipramine (Anafranil®) [a tricyclic]
Approved for OCD
 fluoxetine (Prozac®)
 fluvoxamine (Luvox®)
 paroxetine (Paxil®)
SSRIs
 sertraline (Zoloft®)
 *citalopram (Celexa®)
 *escitalopram (Lexapro®)
 *SNRI antidepressants are also used
*Off label use

12. Treatment of OCD
 Full effects of drug treatment may take 10-12 weeks
 Cognitive Behavioral Therapy (CBT) is effective
 Combination (CBT + drug therapy) may be better
 Treatment is usually chronic
 Partial responders often receive augmentation with
atypical antipsychotic drugs (not an approved
indication for these drugs)

13. Social Anxiety Disorder
 Generalized
 Nearly all social situations
 Discrete
 Performance anxiety

14. Treatment of Social Anxiety Disorder
 SSRI/SNRI
 High potency benzodiazepine (BZD)
 alprazolam
 clonazepam
 MAOIs
 Beta blockers for performance anxiety
 propranolol 10-40 mg one hour before
 Reduces sympathetic symptoms (sweating, tremor)
 +CBT

15. Post-traumatic Stress Disorder (PTSD)
 Traumatic event
 Re-experiencing the event
 Recall, flashback, dreams
 Intense psychological distress with exposure
 Avoidance
 Increased arousal

16. Treatment of PTSD
 SSRI - sertraline and paroxetine approved
 Off label treatments
 Beta blockers to ⇩ autonomic arousal
 Li+ and antiepileptic drugs
 development of PTSD resemblance to “kindling”
 cf. Bipolar Disorder treatments

17. Treatment of Generalized Anxiety
Disorder (GAD)
 Benzodiazepines
 buspirone (Buspar®)
 Antidepressants
 TCA (e.g., imipramine)
 SSRI
 SNRI (venlafaxine, duloxetine)

18. GABA-A Receptor
 Endogenous ligand is GABA
 GABA is the major inhibitory CNS
neurotransmitter
 Opens the Cl- ionophore
 Inhibits neuronal firing
 The GABA-Benzodiazepine receptor complex
 Ligand-gated ion channel
 Selectively conducts Cl- through its pore
 causes hyperpolarization of the neuron

19. GABA-BZD receptor complex
 Benzodiazepines
 Allosterically modulate the GABA receptor
 Potentiate the effect of GABA
 Other substances bind this receptor complex
 e.g., EtOH, barbiturates
 Benzodiazepines increase the frequency of the chloride
ion channel opening at the GABAA receptor
 Barbiturates increase the duration of chloride ion channel
opening at the GABAA receptor

21. Benzodiazepine Indications
 GAD
 Panic Disorder
 EtOH withdrawal
 Hypnotic
 Anticonvulsant
 diazepam, lorazepam
 Preanesthetic, procedural sedation
 midazolam, lorazepam

22. Examples of benzodiazepines
Anxiolytics Brand name Dose range
chlordiazepoxide (Librium®) 10-100 mg
diazepam (Valium®) 2-20 mg
alprazolam (Xanax®) .75-10 mg
lorazepam (Ativan®) .5-10 mg
Hypnotics
flurazepam (Dalmane®) 15-30 mg
triazolam (Halcion®) .125-.25mg

23. Benzodiazepine Adverse Effects
 Sedation
 Effect exploited for use as hypnotics
 Amnesia
 Particularly with triazolam
 Effect exploited for use in anesthesia (midazolam) and
conscious sedation/procedural sedation
 Psychomotor impairment, Ataxia
 Potentiation of alcohol, other CNS depressants
 Risk for dependence
 Withdrawal syndrome

24. Benzodiazepine Intoxication/Overdose
 Intoxication is similar to alcohol
 Sedation
 Psychomotor impairment
 Dizziness/Ataxia
 Amnesia
 Overdose
 All of the above
 Confusion/agitation
 Severe sedation/lethargy
 Respiratory depression
 Unresponsiveness

25. Benzodiazepine Withdrawal
 Anxiety/agitation
 Sleep disturbance
 Myoclonic jerks
 Sensory disturbances
 Paresthesias
 Muscle cramps
 Dizziness
 After high dose usage, withdrawal may include:
 Seizures
 Delirium

26. Drug-drug interactions
 Potentiation of CNS depressants
 BZDs increase the half-life of digoxin
 Increase BZD levels
 cimetidine, disulfiram, isoniazid, estrogen
 Inhibit metabolism
 fluvoxamine ⇧ alprazolam levels (CYP3A4)
 Decrease BZD levels
 Antacids ⇩ absorption
 Tobacco, rifampin (enzyme induction)

27. Benzodiazepine antagonist
 flumazenil (Romazicon®)
 Reverses effects of drugs acting at the benzodiazepine
receptor
 does not antagonize the central nervous system effects of
drugs affecting GABA-ergic neurons by means other than
the benzodiazepine receptor; e.g., ethanol, barbiturates, or
general anesthetics)
 does not reverse the effects of opioids
 used to reverse BZD conscious sedation
 may be useful in suspected BZD overdose
 Onset 1-2 minutes; duration of effect 4-5 hours

28. Non-benzodiazepine Treatments for
Anxiety
 buspirone (Buspar®)
 SSRI
 SNRI
 venlafaxine (Effexor®)
 duloxetine (Cymbalta®)
 clonidine (Catapres®)

29. Non-benzodiazepine Treatments for
Anxiety
 buspirone
 clonidine

30. buspirone
 Presynaptic 5-HT1A full agonist
 Hypothesized 5-HT excess
 ⇩ Neuronal firing
 ⇩ 5-HT synthesis
 Postsynaptic partial agonist
 With 5-HT excess, acts as antagonist
 With 5-HT deficit, acts as agonist
 No effects on BZD-GABA receptor complex

31. buspirone
 Unlike BZD
 Absence of:
 Sedation
 Muscle relaxant properties
 Anticonvulsant effects
 Abuse potential
 Psychomotor performance impairment

32. buspirone
 May be preferred for
 Elderly
 Patients with medical conditions
 May improve sexual dysfunction secondary to
SSRI
 May be antidepressant in higher doses
 Slower onset than BZD
 Full effect may take days to weeks

33. buspirone adverse effects
 Dizziness
 Headache
 Nausea
 Nervousness
 Lightheadedness
 Agitation

34. clonidine
 Alpha-2 agonist

35. clonidine
 NE overactivity can cause anxiety
symptoms
 Alpha-2 antagonists cause ⇧ NE
 Alpha-2 agonist can be anxiolytic
Especially on adrenergic symptoms
 Tachycardia
 Sweating
 Tremor

36. Hypnotics
 OTC – diphenhydramine*
 TCA*
 trazodone (Desyrel®)*
 doxepin (Silenor®) H1 antagonist*
 Benzodiazepines
 Non-benzodiazepine
 Similar GABAergic mechanism
 ramelteon (Rozerem®)*
 melatonin agonist
*Not a controlled substance

37. Examples of Benzodiazepine and
Non-benzodiazepine Hypnotics
Benzodiazepine
 flurazepam (Dalmane®)
 temazepam (Restoril®)
 triazolam (Halcion®)
Non-benzodiazepine
 zolpidem (Ambien®)
 zaleplon (Sonata®)
 zopiclone (Imovane®)
 eszopiclone (Lunesta®)