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					                                                              ANXIETY

-a mental disorder characterized by the perception of danger that threatens the security of an individual
-pathological anxiety:
        - distress not clearly due to an external cause         -persistence over time; chronically
        -high intensity of sxs                                  -development of harmful behavior or coping strategies

-types: -panic disorder (±agoraphobia)         -generalized anxiety disorder (GAD)
        -social anxiety disorder (SAD)         -obsessive-compulsive disorder (OCD)
        -post-traumatic stress disorder (PTSD) -acute stress disorder
        -substance-induced anxiety disorder


                                                        PANIC DISORDER

-Panic Attack:
        -episode of intense fear or discomfort
        -must have at least 4 additional somatic or cognitive symptoms:
-palpitations, pounding heart               -sweating, trembling or shaking              -SOB or choking/feeling of choking
-chest pain or discomfort                   -dizzy, lightheaded, faint                   -fear of losing control or going crazy
-derealization or depersonalization         -nausea or abdominal stress                  -fear of dying
-chills or hot flushes                      -paresthesias
        -symptoms develop suddenly and usually peak within 10 minutes

-Panic Disorder: recurrent unexpected panic attacks

-Anticipatory Anxiety: at least 1 month of worry about recurrence


                                                DSM-IV-TR Criteria
  Panic Disorder ± Agoraphobia
  A. Both of the following:
           1.recurrent unexpected panic attacks
           2.at least 1 of the attacks has been followed by at least 1month of one or more of the following:
           -persistent concern about having another attack
           -worry about the implications of the attack or its consequences
           -a significant change in behavior related to the attacks
  B. Presence (or Absence) of agoraphobia
  C. Attacks are not due to the direct physiologic effects of a substance or general medical condition
  D. Attacks are not better accounted for by another mental disorder


-Criteria for Agoraphobia:
         A. individual has marked fear of and thus avoids being alone or being in public places from which an escape
         might be difficult or help not available in case of sudden incapacitation; fear of having a panic attack

        B. Increasing constriction of normal activities until the fear and avoidance behavior dominates the individual’s
        life; the patient usually needs a companion

        C. The phobia is not better accounted for by another mental disorder

-Epidemiology:
       -onset: bimodal peak in late adolescence and mid-30s
       -twice as common in women as among men
       -10-15% of general population experience a single panic attack during their lifetime
          -lifetime prevalence: 22.7% for panic attacks; 3.7% for panic disorder; 1.1% for panic disorder w/agoraphobia
          -lifetime prevalence of co-morbid major depressive disorder is 50-60%

-Risk Factors:
        -increased by 8x in 1st degree relatives
        -80% of patients report major life stressors during the previous 12 months
        -hx of childhood sexual or physical abuse
        -adolescents who smoke

-Secondary Causes of Panic Disorder:
       -CV: arrhythmia, tachycardia, angina, mitral valve prolapsed
       -Respiratory: COPD exacerbation, asthma attack, PE, carbon dioxide inhalation
       -Endocrine: hyperthyroidism, hypoglycemia, hypo- or hyperparathyroidism, Cushing’s syndrome
       -GI: IBS, PUD, colitis
       -Neurologic: seizure disorder, vertigo, migraine
       -Psychiatric: depression, schizophrenia
       -Drug Related: stimulants, alcohol withdrawal, high dose corticosteroids

-Non-Pharm Therapy:
       -CBT is effective in treating avoidance
       -combo of CBT & pharmacotherapy in panic disorder is more effective than either alone

-Antidepressants:
        -SSRIs-FDA indicated: fluoxetine, paroxetine, paroxetine CR, sertraline
                -data: citalopram, fluvoxamine
        -TCAs-clomipramine and imipramine most studied
        -MAOIs-phenelzine most studied
        -Other antidepressants- FDA indicated: venalfaxine XR
                -data: mirtazapine

-SSRIs:
          -Therapeutics
                  --all SSRIs are effective for the tx of panic disorder
                  --2/3 of patients show clinical improvement across 5 principal domains: (Panic Attacks, Anticipatory
                  Anxiety, Phobic Avoidance, Well-being, Disability)
                  --first line tx due to ↑tolerability and ↓likelihood for physical dependency and withdrawal
          -Pharmacodynamics
                  --requires QD administration
                  --4-6 weeks necessary to reduce frequency of panic attacks
                  --up to 12 weeks needed to assess full response
                  --additional response may be noted for up to 6 months
          -Adverse Effects:
                  --psychiatric/neurologic: anxiety (limited to 1st 8 weeks, so add BZD), insomnia or sedation, HA
                  --GI: nausea, diarrhea, anorexia
                  --sexual dysfunction                             SSRI        Initial Dose Weekly Titration    Usual Daily
                  --sweating                                                   (mg/day)      Dose (mg)          Dose (mg)
                  --serotonin syndrome
                                                                   Fluoxetine  5-10          10                 5-80
          -Dosing: once ↑dose typically don’t ↓if effective
          -smaller initial dose due to anxiety SE                  Paroxetine  10            10                 10-40
          -panic disorder is especially sensitive to it
          -Patient Counseling:                                     Paroxetine  12.5          12.5               25-75
                  --initial response may take up to 4 weeks CR
                  --8-12 weeks to see full response
                                                                   Sertraline  25            25-50              25-200
                  --may take for up to 12-24 months after
                  remission
                  --may increase anxiety or jitteriness initially
                  --must take daily to produce effect; not PRN
                  --may take with food to avoid upset stomach

-SNRIs:
          -Venlafaxine XR –only SNRI approved for Panic Disorder
          -PD’s similar to SSRIs
          -ADE:
                  --psychiatric/neuro: anxiety, dizziness, asthenia, somnolence
                  --GI: nausea, constipation, anorexia, dry mouth
                  --sexual dysfunction
                  --sweating
                  --dose-related HTN (diastolic BP)
          -Dosing:
                  --37.5 mg QD x 1 week
                  --may increase to 75mg QD with subsequent weekly increases of 75 mg/day
                  --MAX 225 mg/day
          -Patient Counseling: similar to SSRIs

-TCAs:
          -Therapeutics:
                  --clinical trials indicate that 45-70% patients become panic free
                  --comparable efficacy to SSRI and BZD, but considered 2nd line due to tolerability
                  --potential lethal in overdose
                  --patients more sensitive to SE of TCAs than SSRIs
          -Pharmacodynamics:
                  --up to 4 weeks partial response
                  --may take 6-10 weeks for anti-phobic response
                  --up to 8-12 weeks for full response
                  --anticipatory anxiety usually resolves after attacks dissipated
                  --requires QD administration, PRN = not effective
          -ADE:
                  --pyschiatric/neurologic: anxiety, jitteriness, sedation
                  --anticholinergic:urinary retention, constipation, blurred vision, dry mouth
                  --CV: orthostatic hypotension, arrhythmias
                  --GI: weight gain, nausea               TCA               Initial Dose     Weekly Titration   Usual Daily Dose
                  --sexual dysfunction                                      (mg/day)         Dose               (mg)
          -Patient Counseling:
                  --avoid etoh & CNS depressants          Imipramine        10               10mg every 2-4     150-300
                  --caution while driving or              (Tofranil)                         days
                  operating machinery
                                                          Clomipramine      25               25mg every 4-5     25-150
                  --relieve dry mouth with sugar-
                                                          (Anafranil)                        days
                  less candy/gum
                  --rise slowly to avoid othrostasis
                  --time delay of effect (12 weeks for full response)
                  --take daily; not PRN
                  --do not stop abruptly

-MAOIs:
       -Therapeutics:
              --no controlled studies for panic disorder
              --last line due to dietary restrictions and DDIs
       -Pharmacodynamics:
               --hypertensive crisis after ingestion of tyramine-containing foods of sympathomimetic meds
        -Phenelzine (Nardil)
               -ADE: sleep disturbances, parethesias, confusional state, blurred vision, dry mouth, hypotension, edema,
               weight gain or anorexia, sexual dysfunction
               -Dosing: 15mg daily after evening meal; increase by 15mg every 3-4 days up to 60mg; MAX 90mg/day
               -Counseling: dietary restrictions, OTC meds, response will be delayed

-Benzodiazepines:
       -Therapeutics:
               --all are effective in anticipatory anxiety associated with panic disorder
               --first line for pts requiring rapid relief
               --alternative agents for pts that cannot tolerate antidepressants
               --often combined with antidepressants on a standing PRN basis
               --drug choice dependent on matching the clinical properties to pts symptomatology
               --Xanax and Klonopin are FDA approved
       -CIs:
               --acute etoh intoxication                   --chronic pulmonary insufficiency
               --significant liver dx (LOT)                --sleep apnea
               --narrow angle glaucoma                     --caution in co-morbid substance abuse
       -PKs:
               --varying t ½ (SA: alprazolam; LA: Klonopin); duration of action; hypatic dysfunction
       -PDs:
               --anxiety relief with one dose
               --anti-panic effect occurs within 1 week
               --additive CNS toxicity with CNS depressants
       -ADEs:
               --sedation                          --anterograde amnesia
               --cognitive impairment              --paradoxical effects (disinhibition) –agitation, anger
               --respiratory depression (pulm) --physical dependence
               --5x more MVA

BZD                             Initial dose                    titration                        usual daily dose (mg)

alprazolam (xanax)              0.25 mg TID                     0.25 – 0.5 mg every 3-4 days     4-6 (10 max)

clonazepam (klonopin)           0.25mg BID                      0.5mg bid on day 4, then         3-6
                                                                0.125-0.25mg BID every 3 days
                                                                PRN

diazepam (valium)               2.5mg TID                       5mg every 3-4 days               30-40

lorazepam (ativan)              0.5mg TID                        by 0.5mg every 3-4 days         3-4

        -Withdrawl syndrome: (may not see withdrawl in 5-10 days for SA, weeks for LA)
               1.frequent: anxiety, insomnia, irritability, muscle aches/weakness
               2. common: nausea, depression, ataxia, hyperreflexia, blurred vision, fatigue
               3. rare: confusion, delirum, pyschosis, seizures

                 -Steps for tapering:
                         1.develop good relationship with patient (must be sx free for 12-24 months)
                         2. do not attempt until pt’s depressive and anxiety sxs have been stabilized. regimen should be
                         individualized.
                         3. Withdrawal typically occurs after at least 4 weeks of chronic use of benzodiazepines.
                         4. Calculate patient’s total daily BZD dose in diazepam equivalents.
                         5. If the patient is receiving greater than 10mg of diazepam or its equivalent, taper only to a
                         level of 10mg per day of diazepam or its equivalent; If the patient is receiving less than 10mg of
                        diazepam or its equivalent, taper by 50% of total daily dose. This first resultant dose reduction
                        should be continued for at least 2-4 weeks.
                        6. After 2-4 weeks, decrease the total daily dose by ~10% per week.
                        7. Alprazolam tapers: Maximum of decrease by 0.5mg every 3 days. May require 0.125-0.25mg
                        adjustments.
                -Patient Counseling:
                        --may experience sedation, difficulty concentrating (1 week)
                        --caution while driving or operating machinery
                        --do not drink etoh
                        --do not d/c abruptly; may cause physical dependence
                        --if used with SSRI can be tapered after 8 weeks

                  Antidepressants                                                    Benzodiazepines

Advantages                Disadvantages                Advantages                              Disadvantages

-co-morbid depression,    -sensitivity to ADE          -rapid onset                            -abuse potential
substance abuse           -delayed effect              -↑compliance with antidepressant        -difficult to d/c
-low abuse potential      -discontinuation syndrome    -inexpensive




                                           GENERALIZED ANXIETY DISORDER



                                                       DSM-IV-TR Criteria
                     -excessive anxiety and uncontrollable worry that persists for at least 6months
                     -3 of the following 6 sxs must be present majority of days:
                               -restlessness              -fatigue
                               -difficulty concentrating -irritability
                               -impaired sleep cycle      -muscle tension




-Epidemiology:
       --onset early 20’s                           --lifetime prevalence 5%
       --1 year prevalence 2.8%                     --women>men

-Therapeutic Goals:
       --decrease anxiety and improve adaptive functioning
       --prevent secondary psychiatric or medical disorders
       --minimize ADE from pharmacotherapy
       --prevent relapse or recurrence
-Nonpharm Therapy:
       --pyschotherapy is cornerstone of tx (CBT, relaxation)
       --pharmacologic therapy has significant impact on daily living

BZDs:
-used to be 1st line, now used for intermittent short-term treatment
-match agent based on pt symptoms
Buspirone(Buspar)
       -Therapeutics:
               --when excess serotonin excess it is a 5HT antagonist, where it is deficit it is an agonist
       -CIs:
               --hypersensitivity
       -PDs:
               --single dose can elevate prolactin levels, but not continuous doses
               --onset of effect is at least 1 month
       -ADEs:
               --asthenia, dizziness, confusional states, HA, hostility, blurred vision, nausea, galatorea
       -Dosing:
                                                              Advantages                   Disadvantages
               --initial dose is 7.5mg BID
               --titrate 5mg/day every 2-3 days
               --target dose is 30mg/day divided BID          -no abuse potential          -long onset of effect
                                                              -no sedation or              -no cross-tolerance with
               --6 week vs 6 month taper
                                                              impairment of motor          BZDs
               --no dose adjustment in elderly                activity                     -patient perception of
       -Counseling:                                           -does not potentiate         lack of response
               --delayed response; at least 1 month           other CNS depressants        -still must taper BZD if
               --take daily; not effective PRN                                             changed to Buspar

Venlafaxine (Effexor)
       -both IR and XR are effective; XR FDA approved
       -most common ADE in GAD clinical trials were nausea, insomnia, dry mouth, and somnolence
       -effective in both short term and long term (6 month) studies

Duloxetine (Cymbalta)
       -CIs:
               --hypersensitivity to duloxetine
               --concomitant use of MAOIs
               --uncontrolled narrow-angle glaucoma
       -PDs:
               --dosing >60mg/day no more efficacious
       -Dosing:
               --initial 30mg daily
               --titrate after 1 week to 60mg daily [MAX]
       -ADEs:
               --fatigue, dizziness, insomnia or somnolence, vertigo, blurred vision, nausea, constipation, anorexia,
               diarrhea, dry mouth, sexual dysfunction, sweating, palpitations
       -Counseling:
               --similar to SSRIs

SSRIs
        -Paroxetine:
               --FDA Indication for GAD
               --no greater efficacy in doses >20mg/day
               --long-term efficacy (24 weeks)
        -Lexapro:
               --FDA approved for GAD
               --10-20 mg daily

Other antidepressants:
       -TCAs- 3rd line due to intolerance; dose same as depression
       -MAOIs: 3rd or 4th line due to intolerance
Anticonvulsants:
       -Pregabalin (Lyrica)
               --approved by European Commission for tx of GAD; not FDA approved
               --long term studies still needed
               --advantage of rapid onset of action (1 week)
               --advantage of less withdrawal vs BZDs
               --SE: somnolence, dizziness, weight gain
       -Tiagabine (Gabitril)
               --open-label vs. paroxetine; not powered to perform comparative statistics

				
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posted:11/17/2011
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