Treatment of Anxiety Treatment of Anxiety DisordersDisorders

time to onset of effectstime to onset of effects Antidepressant drugs are used to Antidepressant drugs are used to treat anxiety disorders. These drugs treat anxiety disorders. These drugs have a latency to onset of clinically have a latency to onset of clinically meaningful effects, typically 3 to 4 meaningful effects, typically 3 to 4 weeks or longerweeks or longer

Benzodiazepines have a rapid onset Benzodiazepines have a rapid onset of effect (30 minutes to one hour)of effect (30 minutes to one hour)

Anxiety DisordersAnxiety Disorders

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

Neurotransmitters Neurotransmitters Implicated in AnxietyImplicated in Anxiety Gamma-amino butyric acid (GABA)Gamma-amino butyric acid (GABA)

GABA-benzodiazepine receptor complexGABA-benzodiazepine receptor complex Norepinephrine (NE)Norepinephrine (NE)

Brainstem locus coeruleusBrainstem locus coeruleus Serotonin (5-hydroxytryptamine, 5-HT)Serotonin (5-hydroxytryptamine, 5-HT)

Anxiolytic DrugsAnxiolytic Drugs

DiscoveryDiscovery meprobamate (1954)meprobamate (1954) chlordiazepoxide (1957)chlordiazepoxide (1957)

First of many benzodiazepinesFirst of many benzodiazepines

Panic DisorderPanic Disorder

With and without agoraphobiaWith and without agoraphobia

Panic attacks (unexpected)Panic attacks (unexpected) Anticipatory anxietyAnticipatory anxiety Generalized anxietyGeneralized anxiety Avoidance (agoraphobia)Avoidance (agoraphobia) Somatic symptomsSomatic symptoms

Pharmacologic Treatment of Pharmacologic Treatment of Panic DisorderPanic Disorder Antidepressants (latency to onset of effects)Antidepressants (latency to onset of effects)

TCAs - imipramine, clomipramineTCAs - imipramine, clomipramine MAOIsMAOIs SSRI/SNRI - first choice for many patientsSSRI/SNRI - first choice for many patients

Benzodiazepines (rapid onset of effects)Benzodiazepines (rapid onset of effects) First choice if rapid effect neededFirst choice if rapid effect needed alprazolam (Xanax®)alprazolam (Xanax®) clonazepam (Klonopin®)clonazepam (Klonopin®)

CombinationsCombinations

Adverse EffectsAdverse Effects SSRI/SNRISSRI/SNRI

Activation - may cause initial jitterinessActivation - may cause initial jitteriness Gradual dose escalation recommendedGradual dose escalation recommended

Sexual dysfunctionSexual dysfunction Gastrointestinal side effectsGastrointestinal side effects Withdrawal syndromeWithdrawal syndrome

BenzodiazepinesBenzodiazepines SedationSedation Potentiation of alcohol, other CNS depressantsPotentiation of alcohol, other CNS depressants DependenceDependence Psychomotor impairment, AtaxiaPsychomotor impairment, Ataxia AmnesiaAmnesia Withdrawal syndromeWithdrawal syndrome

Non-pharmacologic Treatment Non-pharmacologic Treatment of Panic Disorderof Panic Disorder Cognitive Behavioral Therapy (CBT)Cognitive Behavioral Therapy (CBT)

Frequently, pharmacologic treatment and CBT Frequently, pharmacologic treatment and CBT are used in combinationare used in combination

Obsessive Compulsive Obsessive Compulsive DisorderDisorderCommon ObsessionsCommon Obsessions ContaminationContamination AggressionAggression ReligiousReligious Safety/harmSafety/harm Need for symmetryNeed for symmetry Somatic fearsSomatic fears

Common CompulsionsCommon Compulsions CheckingChecking Cleaning/washingCleaning/washing Counting/Mental ritualsCounting/Mental rituals RepeatingRepeating Ordering/arrangingOrdering/arranging HoardingHoarding

Treatment of OCDTreatment of OCD

Drugs that increase synaptic serotoninDrugs that increase synaptic serotonin

Treatment of OCDTreatment of OCDserotonin reuptake inhibitors serotonin reuptake inhibitors (SRIs)(SRIs) clomipramine (Anafranil®) clomipramine (Anafranil®) [a tricyclic][a tricyclic]

fluoxetine (Prozac®)fluoxetine (Prozac®) fluvoxamine (Luvox®)fluvoxamine (Luvox®) paroxetine (Paxil®)paroxetine (Paxil®) sertraline (Zoloft®)sertraline (Zoloft®) **citalopram (Celexa®)citalopram (Celexa®) **escitalopram (Lexapro®)escitalopram (Lexapro®)

**SNRI antidepressants are also usedSNRI antidepressants are also used*Off label use

Appro

ved f

or

OC

D

SSRIs

Treatment of OCDTreatment of OCD

Full effects of drug treatment may take 10-12 weeksFull effects of drug treatment may take 10-12 weeks Cognitive Behavioral Therapy (CBT) is effectiveCognitive Behavioral Therapy (CBT) is effective Combination (CBT + drug therapy) may be betterCombination (CBT + drug therapy) may be better Treatment is usually chronicTreatment is usually chronic

Partial responders often receive augmentation with Partial responders often receive augmentation with atypical antipsychotic drugs (not an approved atypical antipsychotic drugs (not an approved indication for these drugs)indication for these drugs)

Social Anxiety DisorderSocial Anxiety Disorder

GeneralizedGeneralized Nearly all social situationsNearly all social situations

Discrete Discrete Performance anxietyPerformance anxiety

Treatment of Social Anxiety Treatment of Social Anxiety DisorderDisorder SSRI/SNRISSRI/SNRI High potency benzodiazepine (BZD)High potency benzodiazepine (BZD)

alprazolamalprazolam clonazepamclonazepam

MAOIsMAOIs Beta blockers for performance anxietyBeta blockers for performance anxiety

propranolol 10-40 mg one hour beforepropranolol 10-40 mg one hour before Reduces sympathetic symptoms (sweating, tremor)Reduces sympathetic symptoms (sweating, tremor)

+CBT+CBT

Post-traumatic Stress Post-traumatic Stress Disorder Disorder (PTSD)(PTSD) Traumatic eventTraumatic event Re-experiencing the eventRe-experiencing the event

Recall, flashback, dreamsRecall, flashback, dreams Intense psychological distress with exposure Intense psychological distress with exposure

AvoidanceAvoidance Increased arousalIncreased arousal

Treatment of PTSDTreatment of PTSD

SSRI - sertraline and paroxetine approvedSSRI - sertraline and paroxetine approved

Off label treatmentsOff label treatments Beta blockers to Beta blockers to ⇩⇩ autonomic arousalautonomic arousal LiLi++ and antiepileptic drugs and antiepileptic drugs

development of PTSD resemblance to “kindling”development of PTSD resemblance to “kindling” cf. Bipolar Disorder treatmentscf. Bipolar Disorder treatments

Treatment of Generalized Treatment of Generalized Anxiety Disorder (GAD)Anxiety Disorder (GAD) BenzodiazepinesBenzodiazepines buspirone (Buspar®)buspirone (Buspar®) AntidepressantsAntidepressants

TCA (e.g., imipramine)TCA (e.g., imipramine) SSRISSRI SNRI (venlafaxine, duloxetine) SNRI (venlafaxine, duloxetine)

GABA-A Receptor

Endogenous ligand is GABA GABA is the major inhibitory CNS GABA is the major inhibitory CNS

neurotransmitterneurotransmitter Opens the ClOpens the Cl-- ionophore ionophore Inhibits neuronal firingInhibits neuronal firing

The GABA-Benzodiazepine receptor complexThe GABA-Benzodiazepine receptor complex Ligand-gated ion channel Selectively conducts Cl-- through its pore causes hyperpolarization of the neuron

GABA-BZD receptor complexGABA-BZD receptor complex

Benzodiazepines Benzodiazepines Allosterically modulate the GABA receptorAllosterically modulate the GABA receptor Potentiate the effect of GABAPotentiate the effect of GABA

Other substances bind this receptor complexOther substances bind this receptor complex e.g., EtOH, barbituratese.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

Benzodiazepine IndicationsBenzodiazepine Indications

GADGAD Panic DisorderPanic Disorder EtOH withdrawalEtOH withdrawal HypnoticHypnotic AnticonvulsantAnticonvulsant

diazepam, lorazepamdiazepam, lorazepam Preanesthetic, procedural sedationPreanesthetic, procedural sedation

midazolam, lorazepammidazolam, lorazepam

Examples of benzodiazepinesExamples of benzodiazepines

AnxiolyticsAnxiolytics Brand nameBrand name Dose rangeDose range

chlordiazepoxidechlordiazepoxide (Librium®)(Librium®) 10-100 mg10-100 mg

diazepamdiazepam (Valium®)(Valium®) 2-20 mg2-20 mg

alprazolamalprazolam (Xanax®)(Xanax®) .75-10 mg.75-10 mg

lorazepamlorazepam (Ativan®)(Ativan®) .5-10 mg.5-10 mg

HypnoticsHypnotics

flurazepamflurazepam (Dalmane®)(Dalmane®) 15-30 mg15-30 mg

triazolamtriazolam (Halcion®)(Halcion®) .125-.25mg.125-.25mg

Benzodiazepine Adverse Benzodiazepine Adverse EffectsEffects SedationSedation

Effect exploited for use as hypnoticsEffect exploited for use as hypnotics AmnesiaAmnesia

Particularly with triazolamParticularly with triazolam Effect exploited for use in anesthesia (midazolam) and Effect exploited for use in anesthesia (midazolam) and

conscious sedation/procedural sedationconscious sedation/procedural sedation Psychomotor impairment, AtaxiaPsychomotor impairment, Ataxia Potentiation of alcohol, other CNS depressantsPotentiation of alcohol, other CNS depressants Risk for dependenceRisk for dependence Withdrawal syndromeWithdrawal syndrome

Benzodiazepine Benzodiazepine Intoxication/OverdoseIntoxication/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

Benzodiazepine WithdrawalBenzodiazepine Withdrawal Anxiety/agitationAnxiety/agitation Sleep disturbanceSleep disturbance Myoclonic jerksMyoclonic jerks Sensory disturbancesSensory disturbances

ParesthesiasParesthesias Muscle crampsMuscle cramps DizzinessDizziness

After high dose usage, withdrawal may include:After high dose usage, withdrawal may include: SeizuresSeizures DeliriumDelirium

Drug-drug interactionsDrug-drug interactions

Potentiation of CNS depressantsPotentiation of CNS depressants BZDs increase the half-life of digoxinBZDs increase the half-life of digoxin Increase BZD levelsIncrease BZD levels

cimetidine, disulfiram, isoniazid, estrogen cimetidine, disulfiram, isoniazid, estrogen Inhibit metabolismInhibit metabolism

fluvoxamine fluvoxamine ⇧ ⇧ alprazolam levels (CYP3A4)alprazolam levels (CYP3A4)

Decrease BZD levelsDecrease BZD levels Antacids Antacids ⇩⇩ absorption absorption Tobacco, rifampin (enzyme induction)Tobacco, rifampin (enzyme induction)

Benzodiazepine antagonist

flumazenil (Romazicon®) Reverses effects of drugs acting at the benzodiazepine

receptor does not antagonize the central nervous system effects of does not antagonize the central nervous system effects of

drugs affecting GABA-ergic neurons by means other than drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor; e.g., ethanol, barbiturates, or the benzodiazepine receptor; e.g., ethanol, barbiturates, or general anesthetics)general anesthetics)

does not reverse the effects of opioidsdoes 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

Non-benzodiazepine Non-benzodiazepine Treatments for AnxietyTreatments for Anxiety buspirone (Buspar®)buspirone (Buspar®) SSRISSRI SNRISNRI

venlafaxine (Effexor®)venlafaxine (Effexor®) duloxetine (Cymbalta®)duloxetine (Cymbalta®)

clonidine (Catapres®)clonidine (Catapres®)

Non-benzodiazepine Non-benzodiazepine Treatments for AnxietyTreatments for Anxiety buspironebuspirone

clonidineclonidine

buspironebuspirone

Presynaptic 5-HT1A full agonistPresynaptic 5-HT1A full agonist Hypothesized 5-HT excessHypothesized 5-HT excess ⇩⇩ Neuronal firingNeuronal firing ⇩⇩ 5-HT synthesis5-HT synthesis

Postsynaptic partial agonistPostsynaptic partial agonist With 5-HT excess, acts as antagonistWith 5-HT excess, acts as antagonist With 5-HT deficit, acts as agonistWith 5-HT deficit, acts as agonist

No effects on BZD-GABA receptor complexNo effects on BZD-GABA receptor complex

buspironebuspirone

Unlike BZDUnlike BZD Absence of:Absence of:

SedationSedation Muscle relaxant propertiesMuscle relaxant properties Anticonvulsant effectsAnticonvulsant effects Abuse potentialAbuse potential Psychomotor performance impairmentPsychomotor performance impairment

buspironebuspirone

May be preferred forMay be preferred for ElderlyElderly Patients with medical conditionsPatients with medical conditions

May improve sexual dysfunction secondary to May improve sexual dysfunction secondary to SSRISSRI

May be antidepressant in higher dosesMay be antidepressant in higher doses Slower onset than BZDSlower onset than BZD

Full effect may take days to weeksFull effect may take days to weeks

buspirone adverse effectsbuspirone adverse effects

DizzinessDizziness HeadacheHeadache NauseaNausea NervousnessNervousness LightheadednessLightheadedness AgitationAgitation

clonidineclonidine

Alpha-2 agonistAlpha-2 agonist

clonidineclonidine

NE overactivity can cause anxiety NE overactivity can cause anxiety symptomssymptoms

Alpha-2 antagonists cause Alpha-2 antagonists cause ⇧⇧ NE NE Alpha-2 agonist can be anxiolyticAlpha-2 agonist can be anxiolytic

Especially on adrenergic symptomsEspecially on adrenergic symptoms TachycardiaTachycardia Sweating Sweating TremorTremor

HypnoticsHypnotics OTC – diphenhydramine*OTC – diphenhydramine* TCA*TCA* trazodone (Desyrel®)*trazodone (Desyrel®)* doxepin (Silenor®) H1 antagonist*doxepin (Silenor®) H1 antagonist* BenzodiazepinesBenzodiazepines Non-benzodiazepineNon-benzodiazepine

Similar GABAergic mechanismSimilar GABAergic mechanism ramelteon (Rozerem®)*ramelteon (Rozerem®)*

melatonin agonistmelatonin agonist *Not a controlled substance*Not a controlled substance

Examples of Benzodiazepine andExamples of Benzodiazepine and Non-benzodiazepine Hypnotics Non-benzodiazepine Hypnotics

flurazepam (Dalmane®)flurazepam (Dalmane®) temazepam (Restoril®)temazepam (Restoril®) triazolam (Halcion®)triazolam (Halcion®)

zolpidem (Ambien®)zolpidem (Ambien®) zaleplon (Sonata®)zaleplon (Sonata®) zopiclone (Imovane®)zopiclone (Imovane®) eszopiclone (Lunesta®)eszopiclone (Lunesta®)

Benzodiazepine

Non-benzodiazepine