1. Treating Resistant Anxiety Disorders ( Resource: www.healthyminds.org) Lorrin M. Koran, M.D. Professor of Psychiatry, Emeritus Stanford University Medical Center

2. Panic Disorder without Agoraphobia: Diagnostic Criteria Recurrent unexpected panic attacks ≥ 1 month of worry re recurrence, implications, consequences ≥ 1 month of changed behavior Not due to substance or medical disorder Not better accounted for by other psych dx, e.g., PTSD, OCD, social phobia

3. Epidemiology of Panic Disorder Prevalence: 1.6%-2.2%, F/M = 2/1 Age at onset typically 20s Runs in families: –Risk = 4-7x higher in first degree relatives Comorbidities: –Major depression - 50%-60% –Alcohol/substance –GAD, OCD, PTSD –Bipolar I and II - 11%-22%

4. Panic Disorder: Differential Dx Caffeinism Hyperthyroidism COPD Stimulant abuse Hypoparathyroidism Vestibular problem TLE Cardiac arrhythmia Steroids Bronchodilators Pheochromocytoma Hypoglycemia

5. First-line Treatments for Panic Disorder CBT (~ 65% much, very much improved) SSRI ( 50-65% panic free, vs 40-55% placebo ) –Sertraline ≥ 100 mg. Paroxetine 40 mg > 20 mg –Citalopram 20-30 mg > 40-60 mg (  drop outs) Benzodiazepine (60-75% panic free) Add CBT later to SSRI (starting both simultaneously may lead to poorer long-term outcome) Patient education

6. Possible Treatments for Rx-Resistant Panic Disorder Add to an SSRI: –CBT (controlled trials) –high-potency benzodiazepine (dbl.blind trials) –Pindolol (2.5 mg tid) (open trial) –Pramipexole (0.25  1.5 mg/d) (cases) Switch to a TCA (imipramine 75-150 mg) Switch to mirtazapine (1 small trial) Add or switch to an atypical antipsychotic

7. Generalized Anxiety Disorder: Diagnostic Criteria Excessive worry re many events/activities Difficult to control (unlike normal worry) ≥ 50% of days in past 6 months ≥ 3 of: –Muscle tension, restlessness, mental tension, –Fatigue, irritability, poor concentration Causes signif. distress or impairment

8. Epidemiology of Generalized Anxiety Disorder Prevalence 1 year: 3%, lifetime: 5% F/M = 2/1 Onset ≥ 50% in childhood/adolescence Less than 50% remit without Rx About 8% of patients in primary care Comorbidities: –Major depression 63%, dysthymia 40% –Panic disorder, Social Anxiety Disorder, OCD –Sedative, anxiolytic drug abuse –Fibromyalgia, irritable bowel, chest pain, headache

9. First-line Treatments for Generalized Anxiety Disorder SSRI - sexual SEs SNRI - venlafaxine, duloxetine Benzodiazepines - differences among them Buspirone - onset 2-4 weeks. 20-60 mg Hydroxyzine - 50 mg/day, 12-week trial CBT - self-monitor; relaxation; cognitive therapy; rehearse skills via imagery

10. Possible Treatments for Rx-Resistant Generalized Anxiety Disorder Take a caffeine history Consider treatment alliance, comorbid conditions, adherence, secondary gain, stressors, family Add CBT to drug or vice versa (sparse data) Add an SSRI or SNRI to a benzodiazepine (?) Add to an SSRI or SNRI: –A benzodiazepine (experts suggest) –pregabalin (dbl-blnd studies) –an atypical antipsychotic (case reports)

11. Social Anxiety Disorder: Diagnostic Criteria Marked, persistent fear of social situations Fear of embarrassment, humiliation Excessive anxiety in the feared situation Avoids, or endures with great distress Impaired function or marked distress If under age 18, duration ≥ 6 months Not due to BDD, panic, stuttering, anorexia

12. Epidemiology of Generalized Social Anxiety Disorder Prevalence 1 yr: 8%; lifetime 13% F/M = 1.4/1 Onset usually childhood/adolescence Spontaneous remission in only 20% Comorbidities –Major depression - 60% lifetime –Agoraphobia - 47% –Alcohol abuse - 25%-35% –GAD - 20%, panic disorder - 10% –Body dysmorphic disorder - 11%

13. First-line Treatments for Social Anxiety Disorder SSRI (50%-80% response [≥ 50%  in LSAS score]) Venlafaxine (44%-69% response) Benzodiazepine (doesn’t Rx comorbid MDD) CBT (50%-66% response) –Individual format better than group format –? More durable than meds after discontinuation –Doesn’t add to SSRI efficacy in studies, but may help a given individual

14. Possible Treatments for Rx-Resistant Social Anxiety Disorder Add to an SSRI or SNRI (expert opinion): –CBT (individual, not group) –A benzodiazepine –Gabapentin or Pregabalin Switch to an MAOI (controlled trial)

15. Evidence for Anticonvulsants in Anxiety Disorders Mula et al., J Clin Psychopharmacol 2007;27:263-272 DrugGADPanic DisorderSAD Gabapentin2?2 Levetiracetam33 Pregabalin12 Tiagabine3 Topiramate3 Valproic acid33 Level 1 = meta-analysis and replicated RCTs; Level 2 = ≥ 1 RCT; Level 3 = uncontrolled trial with ≥ 10 subjects

16. APA Practice Guideline Work Group on OCD Lorrin M. Koran, M.D., Chair Gregory L. Hanna, M.D. Eric Hollander, M.D. Gerald Nestadt, M.D. Helen Blair Simpson, M.D., Ph.D. APA Staff Robert Kunkle, M.A., Senior Program Manager Amy B. Albert, B.A., Project Manager Laura J. Fochtmann, M.D., Medical Editor

17. Disclosures L. Koran, M.D. –Cypress Bioscience, Eli Lilly, Forest Laboratories, Jazz Pharmaceuticals, Ortho McNeil, Somaxon, E. Hollander, M.D. –Abbott, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Pfizer, Somaxon, Wyeth

18. APA Guideline for Obsessive-Compulsive Disorder: Psychiatric Management Establish a therapeutic alliance. Assess symptoms and differentiate them from those of other disorders. Consider using rating scales. Enhance the safety of the patient and others. Set treatment goals (e.g., to improve symptoms, functioning, QOL; enhance cooperation, coping; educate the patient and family). Enhance treatment adherence.

19. Choosing an Initial Treatment First-line treatments: CBT, SRI, or SRI + CBT. CBT alone is recommended for a patient who is not too depressed, anxious, or severely ill to cooperate with treatment, or who prefers not to take medications. An SRI alone is recommended for a patient who has previously responded well to a given drug or who prefers treatment with an SRI alone.

20. Combined Treatment More effective than monotherapy for some patients, but not necessary for all. Consider for patients with an unsatisfactory response to monotherapy, for those with co- occurring psychiatric conditions for which SRIs are effective, and for those who wish to limit the duration of SRI treatment. Also consider for patients with severe OCD.

21. Comorbid Conditions in OCD Treatment Implications e.g., of tics/Tourette’s

22. Axis I Comorbidity in OCD Subjects Brown Longitudinal Obsessive-Compulsive Study (N=293) LifetimeCurrent DSM-IV Diagnosisn%n% OCD only 27 9.217058.0 Any mood disorder 21774.1 4816.4 Major depressive disorder (MDD) 19767.2 4415.0 Bipolar disorder 8 2.7 2 0.7 Any psychotic disorder 8 2.7 6 2.0 Any anxiety disorder 15452.611138.0 Panic disorder 5418.4 21 7.2 Social phobia 8127.6 5518.8 Specific phobia 5318.1 4314.7 Generalized anxiety disorder 22 7.5 22 7.5 Any substance use disorder 7525.6 17 5.8 Pinto A, et al. J Clin Psychiatry. 2006;67:703-711.

23. Pharmacotherapy for OCD Clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline are FDA-approved. An SSRI is preferred for a first medication trial because the SSRIs have a less troublesome side effect profile than clomipramine. All SSRIs (including citalopram and escitalopram) appear to be equally effective. Consider side effects, drug interactions, past treatment response, and co-occurring general medical conditions.

24. CBT and Other Psychotherapies CBT utilizing primarily behavioral techniques such as exposure and response prevention (ERP) is recommended because it has the best evidentiary support. Some data support Cognitive Therapy. Psychodynamic psychotherapy may help patients overcome resistance to treatment or address interpersonal consequences of OCD. Motivational interviewing and family therapy may be useful.

25. Implementing Pharmacotherapy Initiate at the dose recommended by the manufacturer and titrate to the maximum tolerated dose. Continue for 8-12 weeks, including 4-6 weeks at a maximum tolerated dose. Manage side effects (e.g., insomnia, fatigue, sweating, bruxism, sexual dysfunction). Follow-up may vary from a few days to 2 weeks after starting a new medication.

27. Implementation of CBT The literature and expert opinion suggest that an adequate trial for most patients is 13-20 weekly sessions with daily homework (or 3 weeks of weekday daily CBT). CBT can be delivered in individual, group, or family formats, with session lengths from <1 hour to 2 hours. Consider booster sessions after response. Self-help treatment guides are OK to use. Refer patients to www.ocfoundation.org.

28. Changing Treatment: General Principles First treatments rarely produce freedom from all OCD symptoms. Patients may be willing to accept residual symptoms. But consider whether depressed mood is diminishing hopefulness or illness is associated with secondary gain. Consider contribution of other factors such as problems in the therapeutic alliance, interference of co-occurring conditions, inadequate adherence, psychosocial stressors, or family accommodation.

29. Changing Treatment: Strategies Augment SSRI with CBT (or CT) or vice versa. Augment SSRI with an atypical antipsychotic. Switch to a different SSRI or to clomipramine. Switch to venlafaxine or to mirtazpine. Augment with buspirone, once-weekly morphine, inositol, or a glutamate antagonist. Switch to d-amphetamine, tramadol, ondansetron, or an MAOI. Consider rTMS, deep brain stimulation, ablative neurosurgery.

30. Discontinuing Treatment Continue medication for 1-2 years, then consider a gradual taper (10%-25% q 1-2 months). Follow successful CBT with monthly booster sessions for 3-6 months or more. Relapse rates are high. Most patients require continued treatment of some form. Some data suggest “relapse” 4-6 months after CBT is less likely than after medication has been stopped.

31. Additional Information Available in the Full-Text Guideline Disease definition Epidemiology Natural history and course Genetics Review of evidence regarding all treatments Suggestions for future research Published in Am J Psychiatry, July 2007, and www.psychiatryonline.com. www.psychiatryonline.com