PRITE Review of the Anxiety Disorders

1. PRITE Review of the Anxiety Disorders Kimberly D. Law, MD, MPH LSU/Ochsner Psychiatry Residency Program Slides Courtesy of Erich J. Conrad MD Assistant Professor of Clinical Psychiatry

2. Discrete period of intense fear or discomfort in which four or more of the following develop abruptly and reach a peak within 10 minutes: Palpitations or accelerated heart rate Sweating Trembling or shaking Sensations of shortness of breath or smothering Feeling of choking Chest pain or discomfort Nausea or abdominal distress Feeling dizzy, unsteady, lightheaded or faint Derealization or depersonalization Fear of losing control or going crazy Fear of dying Paresthesias Chills or hot flashes PANIC ATTACK

3. PANIC • A panic attack doesn’t equal panic disorder. • Major Depression • Post Traumatic Stress Disorder • Social Phobia • Obsessive Compulsive Disorder • Specific Phobia • Panic Disorder • Recurrent unexpected panic attacks • At least one of the attacks has been followed by one month of 1 or more of the following: • Persistent concern about having additional attacks • Worry about implications of the attack (losing control, having a heart attack, “going crazy”) • Significant change in behavior related to the attacks • With or without agoraphobia

4. Epidemiology • Lifetime prevalence rate: • Panic disorder: 1.5 – 5% • Panic attacks: 3 – 5.6% • Women 2-3 x more likely to be affected than men • Mean age of presentation: 25 years old

5. Amygdala Lateral Nucleus Central Nucleus of the Amygdala Sensory Thalamus Hippocampus Basal Parabrachial Nucleus Hypothalamus Paraventricular Lateral Nucleus Nucleus Periaquaductal Gray Region Nucleus of the Solitary Tract Locus Ceruleus Neuroanatomical Pathways of Viscerosensory Information in the Brain Medial Prefrontal Cortex, Cingulate Association Bundle Insula PituitaryAutonomic Pathways Adrenal Pathways Adapted from: Gorman J, et al. AJP 2000;157:493-505 Visceral Pathways

6. Panic Neurotransmitters Norepinephrine Serotonin GABA GABA • Brain stem:fires off systemically to create autonomic symptoms • Amygdala and Limbic System:generates anticipatory anxiety • Pre-frontal cortex:generates phobic avoidance

7. Cardiovascular Disease Angina CHF Hypertension Mitral valve prolapse Myocardial Infarction Paradoxical atrial tachycardia Pulmonary Disease Asthma Pulmonary embolism Drug intoxication or withdrawal Neurological Disease CVA / TIA Epilepsy Meniere’s disease Migraine Tumor Endocrine Disease Carcinoid syndrome Hyperthyroidism Perimenopausal Pheochromocytoma Other SLE Systemic infection Heavy metal poisoning Differential Diagnosis

8. Course of Illness • 30 – 40 % become symptom free • 50 % with mild symptoms with little impairment of function • 10 – 20 % continue with significant impairment • Depression: 40 – 80 % • Substance abuse: 20 – 40 %

9. Treatment • SSRIs • Benzodiazepines • Cognitive Behavioral Therapy • TCAs • MAOIs • Other agents • Anticonvulsants • Buspirone • Atypical neuroleptics

10. Efficacy of Antidepressants in the Anxiety Disorders1Double-Blind, Placebo-Controlled Studies Panic Agoraphobia Social Specific GAD OCD PTSD Phobia Phobia TricyclicsYes Yes * * Yes Yes Yes2 SSRIsYes Yes Yes * Yes Yes Yes Atypical Nefazodone ** * * * * * Trazodone * * * * Yes2 * * Venlafaxine Yes * Yes * Yes * * Buproprion * * * * * * * Duloxetine * * * * Yes * * MAOIsYes Yes Yes * * *4 Yes2,3 *No Data 1Indicates either no existing data or lack of efficacy in published trials 2Modest or temporary effects reported; 3Based on only 1 study 4One report of efficacy in double-blind comparison to clomipramine (no placebo)

11. Generalized Anxiety Disorder

12. GAD • 1 year prevalence: 3 – 8 % • Lifetime prevalence: 5 % • Ratio of women to men = 2 : 1 • Comorbidity: • 50 – 90 % of GAD patients have another psychiatric disorder • 25 % develop panic disorder

13. DSM-IV Criteria for GAD • Excessive anxiety and worry occurring more days than not for at least 6 months, about a number of events or activities • Person finds it difficult to control the worry • Anxiety and worry are associated with 3 or more of the following: • Restlessness or feeling keyed up or on edge • Easily fatigued • Difficulty concentrating or mind going blank • Irritability • Muscle tension • Sleep disturbance • Focus of anxiety or worry not confined to features of another axis I disorder • Causes significant distress or impairment • Disturbance not due to substance or general medical condition

14. Generalized Anxiety Disorder • Neuroanatomic models poorly developed • Probably: • Limbic and paralimbic structures involved as in panic as well as prefrontal hyperactivity • Represent attempt to suppress subcortically mediated anxiety • Neurochemical • Reduced CSF serotonin • m-chlorophenylpiperazine (m-CPP) • Serotonin agonist, increases anxiety and hostility • SSRIs appear effective in pharmacotherapy • Reduced GABA/Benzodiazepine receptor binding capacity normalizes with treatment

15. GAD • Age of onset: “For as long as I can remember.” • Usually seek treatment in 20s • Only 1/3 seek psychiatric help • Often seen by family practitioners and specialists for somatic complaints of disorder • Chronic and managed over a lifetime • Development of Major depression or Panic disorder often reason for initial presentation

16. Treatment • Psychotherapy • Cognitive behavioral • Supportive • Psychodynamic • Pharmacotherapy • Benzodiazepines • SSRIs • Buspirone • TCAs • Anticonvulsants (GABA)

17. Social Anxiety Disorder

18. Social Anxiety Disorder • A. Marked and persistent fear of one or more social or performance situations. • B.Exposure almost invariably provokes anxiety (including panic attacks). • C. Recognition that the fear is excessive or unreasonable. • D.Situations are avoided or endured with intense anxiety. • E.Symptoms interfere significantly with the person’s • function. • F. Duration is at least 6 months. • G.Not due to medical condition or another mental disorder. • Specify If: • Generalized or Specific

19. The Life Cycle of Anxiety Behavioral Stable Childhood Social Panic Inhibition behavioral anxiety phobia Disorder inhibition Reactive infant Peripheral in play Separation anxiety Social avoidance Onset of panic disorder Inhibited Toddler Retreat from the unfamiliar Shy, tearful Social Fears Social phobia Age yrs .3 2 5 8 13 14-18 20 30 Adapted from: Pollack, et al., Psych Clin NA, 1995;18(4):785-801

20. Social Anxiety Disorder • Lifetime prevalence rate: 7 – 13% • Onset usually in adolescence: mean 15.5 y/o • Male to female ratio - 2:3 • Chronic course with mean duration of 25 years with low rates of recovery • Lifetime rates of comorbid depression near 60% • Rates of comorbid alcohol dependence near 40% • Severe educational, occupational and interpersonal functional impairments

21. Medication Choice • Blanco C, Schneier FR, Schmidt A, et al. Pharmacologic Treatment of Social Anxiety Disorder: A Meta-Analysis Depression and Anxiety 18 (2003) 29-40 • Medication effect size: • Phenelzine: 1.02 [0.52-1.52] • Clonazepam: .97 [0.49-1.45] • Gabapentin: .78 [0.29-1.27] • SSRIs: .65 [0.50-0.81] • No statistical difference between medication groups • Venlafaxine XR not included due to unpublished data

22. Obsessive Compulsive Disorder

23. Either obsessions or compulsions: Obsessions as defined by (1), (2), (3), and (4): Recurrent and persistent thoughts, impulses, or images that are experienced, at some time during the disturbance, as intrusive and inappropriate and that cause marked anxiety or distress The thoughts, impulses, or images are not simply excessive worries about real-life problems The person attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize them with some other thought or action The person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind (not imposed from without as in thought insertion) Compulsions as defined by (1) and (2): Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly (2) The behaviors or mental acts are aimed at reducing distress or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive DSM-IV-TR

24. DSM-IV-TR B. At some point in the disorder, person recognizes obsessions or compulsions are unreasonable (Does not apply to children) C. Obsessions or compulsions cause marked distress, are time consuming, or significantly interfere with functioning D. If another axis I disorder is present, the content of the obsession or compulsion is not restricted to it (trichotillomania, body dysmorphic disorder, hypochondriasis, paraphilia, MDE) E. Disturbance is not due to a substance or general medical condition Specify if: With poor insight

25. OCD • Lifetime prevalence = 2-3% • Adults: Men = Women • Adolescents: boys > girls • Mean age of onset: • Men – 19 years old • Women – 22 years old • Comorbid: • MDE – 67% • Social phobia – 25%

26. OCD • What did Freud think? • Lady Macbeth “The washing was symbolic, designed to replace by physical purity the moral purity which she regretted having lost” • “The Rat Man” • Ernst Lanzer – a prominent young lawyer in Vienna • obsessive thoughts of torture in which a criminal was tied up and a metal pot filled with rats was fastened to his buttocks. The rats would bore their way into the victim’s rectum • Anal = fear of losing control

27. Conditions Associated With OCD • Tourette’s Disorder • Similar age of onset • 90% of patients with Tourette’s have compulsive symptoms • Up to 2/3 of Tourette’s patients meet OCD criteria • 7% of OCD patients have Tourette’s • Hypochondriasis • Body Dysmorphic Disorder • (Impulse control disorders such as kleptomania and pathological gambling)

28. Conditions Associated With OCD • PANDAS • “Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections” • Group A B-hemolytic Streptococcus infection associated with onset of OCD in some children • Autoantibodies react with basal ganglia in Sydenham’s chorea which is also associated with OCD symptoms • Case reports of elimination of symptoms following IVIg

29. Serotonin Hypothesis 1960s: Clomipramine observed to have antiobsessional activity 50% of OCD patients challenged with proserotonergic compounds experience transient worsening of symptoms Suggest basal hyperactivity of 5-HT neurotransmission system, owing to either a hyperactivity of postsynaptic receptors or to a hypoactivity of presynaptic, self-regulatory receptors Possible explanation for both worsening of OCD after acute 5-HT stimulation and clinical efficacy after chronic administration of proserotonergic compounds SSRIs Enhance 5-HT release in orbitalfrontal cortex Desensitization of terminal 5-HT autoreceptors Latency of effect (6-8 weeks) High dosages required Pathophysiology of OCD

30. Pathophysiology of OCD • Dopamine Hypothesis • Correlation between OCD and Tourette’s • Tourette’s appears to be dopaminergically mediated and responds to dopamine antagonists • Patients with comorbid tics often do not respond to proserotonergic compounds • Treatment refractory OCD often aided by neuroleptic augmentation

31. Pathophysiology of OCD • PET studies • Activation of paralimbic circuits, posterior medial orbitalfrontal cortex, anterior cingulate and temporal limbic regions associated with all anxiety conditions • Activation of anterior orbitalfrontal cortex and caudate nucleus specific for OCD • Cortico-strato-thalamo-cortico network • Probable involvement of glutamate, GABA, DA and 5-HT

32. OCD Treatment • Clomipramine and SSRIs • 40% have no clinical improvement • 60% with 25 – 35% decrease in symptoms • (considered a response on Yale-Brown Obsessive Compulsive Scale {Y-BOCS}) • FDA approved in adults: • Clomipramine, Fluoxetine, Fluvoxamine, Sertraline, Paroxetine • FDA approved in pediatrics: • Clomipramine, Fluvoxamine, Sertraline

33. Augmentation: Li (?) Buspirone (?) Trazodone Atypicals Clonazepam rTMS (?) Psychosurgery IV clomipramine OCD Treatment

34. OCD Treatment • Cognitive Behavioral Therapy • OCFoundation

35. Post Traumatic Stress Disorder

36. The person has been exposed to a traumatic event in which both of the following were present: The person experienced, witnessed, or was confronted with an event that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others 2. The person’s response involved intense fear, helplessness, or horror. Note: In children, this may be expressed instead by disorganized or agitated behavior. DSM-IV-TR

37. The traumatic event is persistently reexperienced in one or more of the following ways: Recurrent and intrusive distressing recollections of the event Recurrent distressing dreams of the event Acting or feeling as if the traumatic event were recurring Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the event Physiologic reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the event Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness, as indicated by three or more of the following: Efforts to avoid thoughts, feelings or conversations associated with the trauma Efforts to avoid activities, places or people that arouse recollections of the trauma Inability to recall important aspect of the trauma Markedly diminished interest in significant activities Feelings of detachment or estrangement from others Restricted range of affect Sense of a foreshortened future DSM-IV-TR

38. Persistent symptoms of increased arousal, as indicated by two or more of the following: Difficulty falling or staying asleep Irritability or outbursts of anger Difficulty concentrating Hypervigilance Exaggerated startle response Duration of the disturbance is more than one month Disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning DSM-IV-TR

39. PTSD • Lifetime prevalence • Approximately 8% • 10 – 12% women, 5 – 6% men • Additional 5 – 15% may experience subclinical form of disorder • Predisposing vulnerability factors • Childhood trauma, cluster B personality disorder traits, inadequate support system, being female, genetic vulnerability to psych illness, recent stressful life changes, perception of external locus of control

40. PTSD • Biologic considerations • Noradrenergic system • Increased 24 hr urine epinephrine concentrations • Platelet α2 receptors downregulated • chronically elevated catecholamine • HPA axis • Hyperregulation of HPA axis in PTSD • Low plasma and urinary free cortisol • Exogenous CRF yields blunted ACTH response • Suppression of cortisol with dexamethasone is enhanced in PTSD

41. PTSD • Biologic considerations • MRI, PET studies implicate reduced volume and function of hippocampus in PTSD

42. PTSD • Treatment • SSRIs • Atypicals, benzos • CBT • (EMDR – eye movement desensitization and reprocessing)

43. Review Questions • Hyperthyroidism should be ruled out as part of the differential diagnosis of which of the following psychiatric disorders? a. Cataplexy b. Panic Disorder c. Paranoid Schizophrenia d. Dissociative Identity Disorder e. OCD • Which of the following SSRIs has the longest half-life? a. Sertraline b. Paroxetine c. Fluoxetine d. Citalopram e. Fluvoxamine • Which of the following benzodiazepines does not have active metabolites? a. Diazepam b. Halazepam c. Lorazepam d. Chlorazepate e. Chlordiazepoxide

44. Review Questions • A young adult male patient has thoughts of killing his girlfriend. Whenever he thinks of her, he is suddenly confronted with images of stabbing her in the face. He is extremely upset by these images, which he finds contrary to his own beliefs of nonviolence. In response to these images, he becomes anxious. He relieves his anxiety by pricking his own face with a pin 10 times. This activity occurs now 20 to 30 times per day, and his face is sore and red. The medication most likely to reduce these symptoms is: a. Risperidone b. Lorazepam c. Bupropion d. Buspirone e. Fluvoxamine • A 30-year-old patient has been treated for unreasonable fear of eating in public places, feeling embarrassment in public places, and anger over the possibility of being scrutinized. The patient has responded to high doses of paroxetine, citalopram, buspirone, and alprazolam, each of them administered for 4 to 6 weeks. Which of the following medications would be appropriate for the psychiatrist to consider prescribing next? a. Bupropion b. Fluoxetine c. Mirtazapine d. Phenelzine

45. Review Questions • Which of the following benzodiazepines has an active metabolite? a. Lorazepam b. Temazepam c. Oxazepam d. Chlordiazepoxide • A 25-year-old patient is evaluated for hoarding, intrusive thoughts, and frequent handwashing, which started 2 years ago and now interferes with daily life. In addition to psychotherapy, which of the following medications would be most appropriate to begin? a. Bupropion b. Olanzapine c. Clomipramine d. Mirtazapine e. Alprazolam • Which of the following symptoms would be most commonly associated with Tourette’s Syndrome? a. Somatization b. Panic attacks c. Violent behavior d. Psychotic thinking e. Obsessions and Compulsions

46. Review Questions • Which of the following medications has the least protein binding? a. Fluoxetine b. Sertraline c. Paroxetine d. Venlafaxine e. Clomipramine • Obsessive-compulsive symptoms are characterized by which of the following psychological defense mechanisms? a. Ambivalence and magical thinking b. Displacement and sublimation c. Regression and projection d. Denial and introjection e. Isolation and undoing • Which of the following is a principal goal of the CBT of panic disorder? a. Learning to use biofeedback techniques b. Mastering relaxation in the face of flooding c. Learning more adaptive defenses d. Using restructured interpretation of disturbing sensations