Symptoms/signs (see Box 9.1) \200 Physical symptoms/signs related to autonomic arousal (e.g. tremor, tachycardia, tachypnoea, hypertension, sweating, GI upset), often compounded by HVS (in 50 \200\22360% of cases, se e b p. 356). Concerns of death from cardiac or respiratory problems may be a major focus, l eading to patients presenting (often repeatedly) to emergency medical services. Panic disor der may be undiagnosed in patients with \200\230unexplained \200\231 medical symptoms (che st pain, back pain, GI symptoms including IBS, fatigue, headache, dizziness, or multiple sy mptoms). Thoughts of suicide (or homicide) should be elicited; acute anxiety (particularly when recurrent) can lead to impulsive acts (usually directed towards self). Note: risk of a ttempted suicide substantially raised where comorbid depression, or alcohol or substance mi suse. Epidemiology3 Lifetime prevalence (NCS-R): 1.5 \200\2233.7% for panic disorder, 7 \200\2239 % for panic attacks. Rates much higher in medical clinic samples, e.g. dizziness clinics (1 5%), cardiac clinics (16 \200\22365%), HVS clinics (25 \200\22335%). Women are 2 \200\2233 times more likely to be affected than men. Age of onset has a bimodal distribution with hig hest peak incidence at 15 \200\22324yrs and a second peak at 45 \200\22354yrs. Rare after a ge 65 (0.1%). Other risk factors include: being widowed, divorced, or separated; living in a city; limited education; early parental loss; physical or sexual abuse. Comorbidity Agoraphobia (community surveys: 30 \200\22350%; psychiatric clinics: 75%), depr essive disorder (up to 68%), other anxiety and related disorders (up to 50% \200\224e.g. so cial phobia, OCD), alcohol (up to 30%) and substance mis- use, bipolar affective disorder ( 20%), medical conditions (e.g. mitral valve prolapse, hypertension, cardiomyopathy, COPD, H VS, IBS, migraine). 09_Semple_Chap09.indd 358 12/7/2012 3:34:07 PM PANIC DISORDER 1: CLINICAL FEATURES 359 Differential diagnosis Other anxiety or related disorder (panic attacks may be part of the dis- order), substance or alcohol misuse/withdrawal (e.g. amfetamines, caf- feine, cannabis , cocaine, theophylline, sedative-hypnotics, steroids), mood disorders, psychiatric disorde rs secondary to medical conditions, medical conditions presenting with similar symptoms (e. g. endocrine: carcinoid syndrome, Cushing \200\231s disease/syndrome, hyperthyroidism, hypo glycaemia, hypoparathyroidism, phaeochromocytoma; hematological: anemia; car- diac: arrhyth mias (supraventricular), atypical chest pain, mitral valve pro- lapse, MI; respiratory: COP D, asthma, HVS; neurological: epilepsy \200\224esp. TLE, vestibular dysfunction). Investigations No speci \201 c tests for panic disorder; basic investigations should be pe r- formed to exclude physical causes (e.g. FBC, U&Es, glucose, TFTs, ECG; if supported by h istory/physical examination: toxicology, Ca2+, urinary vanillyl mandelic acid [VMA]/plasma homovanillic acid [pHVA], echo, and EEG). Box 9.1 Symptoms associated with panic attacks In order of frequency of occurrence: \200 \200 \200 \200 \200 \200 \200 \200 \200 Palpitations, pounding heart, or accelerated heart rate. Sweating. Trembling or shaking. Se nse of shortness of breath or smothering. Feeling of choking or dif \201 culties swallowin g (globus hystericus). Chest pain or discomfort. Nausea or abdominal distress. Feeling dizz y, unsteady, light-headed, or faint. Derealization or depersonalization (feeling detached f rom oneself or one \200\231s surroundings). Fear of losing control or going crazy. Fear of dying (angor animus). Numbness or tingling sensations (paraesthesia). Chills or hot \202 ashes. \200 \200 \200 1 \200\230Panic \200\231 derives from the Greek god Pan, who was in the habit of frighteni ng humans and animals \200\230out of the blue \200\231. 2 ICD-10 and DSM-IV disagree on na ture of panic disorder. ICD-10 regards true panic attacks as not being situational, and DSM -IV allows for both spontaneous and situational. Hence, DSM-IV includes agoraphobia within panic disorder, as a special case of situational panic disorder (panic disorder with agorap hobia), whereas ICD-10 separates agoraphobia (under the rubric \200\230phobic anxi- ety di sorders \200\231) from panic disorder (under the rubric \200\230other anxiety disorders \200\231). \200\230Agoraphobia with panic disorder \200\231 allowed in ICD-10 when there i s avoidance of places or situations where to have a spontaneous panic attack would be dif \201 cult or embarrassing. 3 Kessler RC, Chiu WT, Jim R, et al. (2006) The epidemiology of panic attacks, panic disorder, and agoraphobia in the national comorbidity survey replicati on. Arch Gen Psychiat 63: 415 \200\22324. 09_Semple_Chap09.indd 359 12/7/2012 3:34:07 PM CHAPTER 9 Anxiety and stress-related disorders 360 Panic disorder 2: aetiological models A number of theories, based primarily on successful p harmacological treatment, explain the biological basis of panic disorder. \200 The serotonergic model: to synaptic serotonin, possibly s to subsensitivity (reduced bindin g) at 5-HT1A receptors and 5-HT transporters. The noradrenergic model: hypersensitivity of presynaptic affects the hypothalamic \200\223pituitary \200\223adrenal axis and the \201 ring rate is increased in panic.) The GABA model: decreased inhibitory receptor sensit ivity (impaired GABA neuronal response to BDZs), with resultant excitatory effect. Cholecys tokinin \200\223pentagastrin model: dose-dependent fashion in patients with panic disorder. Gene studies also implicate CCK gene polymorphisms in panic disorder (see The genetic hypo thesis). The lactate model: postulated aberrant metabolic activity induced by lactate, from studies involving exercise-induced panic attacks (replicated by IV lactate infusion). The false suffocation carbon dioxide hypothesis: phenomena by hypersensitive brainstem receptor s. The neuroanatomical model: by an overactive \200\230fear network \200\231 in the brain that involves the amygdala, hippocampus, periaqueductal gray, locus coeruleus, thalamus, ci ngulate, and orbitofrontal areas. exaggerated post-synaptic receptor response increased adrenergic activity, with 2 receptors. (Locus coeruleus activity pentagastrin induces panic in a explains panic suggests that panic attacks are mediated The genetic hypothesis Panic disorder has moderate heritability of around 25 \200\22350% (f rom family and twin studies). Most studies to date suggest that vulnerability is genetic- a lly determined, but critical stressors are required to develop clinical symptoms (e.g. sepa ration/loss event, adjusting to a new role, relation- ship problems, physiological stress: childbirth, surgery, hyperthyroidism). Replicated linkages have been found with chromosomes 13q, 22q, 7p, and 9q31. Candidate genes include ADOR2A, 10832/T, CCK and those coding for 5-HT1A, 5-HT2A, COMT, and linked to the CRH gene.1 09_Semple_Chap09.indd 360 12/7/2012 3:34:07 PM PANIC DISORDER 2: AETIOLOGICAL MODELS 361 1 Arnold PD, Zai G, Richter MA (2004) Genetics of anxiety disorders. Curr Psychiat Rep 6: 2 43 \200\22354. 09_Semple_Chap09.indd 361 12/7/2012 3:34:07 PM CHAPTER 9 Anxiety and stress-related disorders 362 Panic disorder 3: management guidelines Combination of pharmacological and psychological tr eatments may be superior to single approach. Choice of initial approach will depend upon pa tient preference, past history of previous bene \201 t, costs, and availability (as well a s local guidelines, e.g. NICE guidance CG113).1 For emergency treatment of a panic attack, see Box 9.2. Pharmacological Current evidence does not suggest any superior ef \201 cacy between SSRIs, SNRIs, BDZs, TCAs, and MAOIs. Other factors will determine the choice of medication (see b p. 266). \200 SSRIs: in the UK citalopram (20 \200\22330mg), escitalopram (5 \200\22310mg), paroxetine (1 0 \200\22340mg), and sertraline (50 \200\223200mg) are all licensed for panic disorder (and recommended as 1st line by NICE). In view of the possibility of initially increasing panic symptoms, start with lowest possible dose and gradually increase. Evidence of bene \201 c ial effect may take up to 12wks and high doses may be necessary. Alternative antidepressant s (unlicensed in the UK): (e.g. venlafaxine), TCAs (e.g. imipramine, clomipramine), MAOIs ( e.g. phenelzine) \200\224thought by some clinicians to be superior to TCAs (for severe, chr onic symptoms), RIMAs (e.g. moclobemide). BDZs NICE. Should be used with caution (due to po tential for abuse or dependence and cognitive impairment), but may be effective for severe, frequent, incapacitating symptoms. Use for 1 \200\2232wks in combination with an antidepre ssant may \200\230cover \200\231 symptomatic relief until the antidepressant becomes effec tive. Note: \200\230anti-panic \200\231 effects do not show tolerance, although sedative e ffects do. Limited bene \201 t: mirtapazine, inositol, reboxetine, atypical antipsychotics , anticonvulsants, and, perhaps surprisingly, propranolol. Second-line treatment: consider change to a different class agent (i.e. TCA, SNRI, SSRI, MAOI), addition of BDZ (or a diffe rent BDZ), trial of bupropion, or for severe symptoms an atypical antipsychotic (e.g. olanz apine or risperidone). If successful: discontinuation (gradually tapering of dose over 2 \200\2234mths). Do not confuse \200\230withdrawal \200\231 effects (10 \200\22320% of pati ents) with re-emergence of symptoms (50 \200\22370% of patients). If symptoms recur, contin ue for 71yr before considering second trial discontinuation. (Note: patient may wish to con tinue treatment, rather than risk return of symptoms). SNRIs (e.g. alprazolam or clonazepam): not recommended by little evidence to support use of bupropion, continue treatment for 12 \200\22318mths before trial Psychological \200 CBT \200\224behavioral methods : to treat phobic avoidance by exposure, use of relaxation, and control of hyperventilation (have been shown to be 58 \200\22383% effective).2 Cognitiv e methods: teaching about bodily responses associated with anxiety/education about panic at tacks, modi \201 cation of thinking errors.3 09_Semple_Chap09.indd 362 12/7/2012 3:34:07 PM PANIC DISORDER 3: MANAGEMENT GUIDELINES 363 Psychodynamic psychotherapy: psychotherapy, particularly \200\230emotion-focused \200\231 treatment (e.g. \200\230panic- focused psychodynamic psychotherapy \200\231),4 where typic al fears of being abandoned or trapped are explored. there is some evidence for brief dynamic Issues of comorbidity \200 In view of high levels of comorbidity, treatment of these conditions should not be neglecte d. For the other anxiety disorders and depression, this issue is somewhat simpli \201 ed b y the fact that SSRIs and other antidepressants have been shown to be effective for these c onditions, too. However, behavioral interventions (e.g. for OCD, social phobia) should also be considered. Alcohol/substance abuse may need to be addressed \201 rst, but speci \201 c treatment for persistent symptoms of panic ought not to be overlooked. Course \200 Most patients seeking treatment have already experienced chronic symptoms for 10 \200\22315 yrs. Untreated, the disorder runs a chronic course. With treatment, functional recovery is seen in 25 \200\22375% after the \201 rst 1 \200\2232yrs, falling to 10 \200\22330% after 5yrs. Long-term, around 50% will experience only mild symptoms. Poor responses associated with: very severe initial symptoms, marked agoraphobia, low socio-economic status, less edu cation, long duration of untreated symptoms, restricted social networks (including loss of a parent, divorce, remaining unmarried), and presence of personality disorder. \200 Box 9.2 Emergency treatment of an acute panic attack \200 Maintain a reassuring and calm attitude (most panic attacks resolve spontaneously within 30 min). If symptoms are severe and distressing consider prompt use of BDZs (immediate relief of anxiety may help reassure the patient, provide con \201 dence that treatment is possibl e, and reduce subsequent \200\230emergency \200\231 presentations). If \201 rst presenta tion, exclude medical causes (may require admission to hospital for speci \201 c tests). I f panic attacks are recurrent, consider differential diagnosis for panic disorder and addre ss underlying disorder (may require psychiatric referral). 1 For full NICE guidance see: http://www.nice.org.uk/nicemedia/live/13314/52599/52599.pdf ( issued Jan. 2011) 2 Ballenger JC et al. (1997) Panic disorder and agoraphobia. In Treatment s of psychiatric disorders, vol. 2, 2nd edn, pp. 1421 \200\22352. Washington, DC: American Psychiatric Press. 3 Barlow DH and Craske MG (1988) Mastery of your anxiety and panic. Stat e University for New York at Albany, Center for Stress and Anxiety Disorders. 4 Milrod B, L eon AC, Busch E, et al. (2007) A randomized controlled clinical trial of psychoanalytical p sychotherapy for panic disorder. American Journal of Psychiatry 164: 265 \200\22372. 09_Semple_Chap09.indd 363 12/7/2012 3:34:07 PM CHAPTER 9 Anxiety and stress-related disorders 364 Agoraphobia1 Essence Anxiety and panic symptoms associated with places or situations where escape may be dif \201 cult or embarrassing (e.g. of crowds, public places, trav- elling alone or away from home), leading to avoidance. Epidemiology2 Prevalence (6mths) 2.8 \200\2235.8% (ECA); 4:5 = 1:3; as for panic disorder, there is bimodal distribution, with the \201 rst being somewhat broader (15 \200\22335yrs ). In later life agoraphobic symptoms may develop s to physical frailty, with associated fe ar of exacerbating medical problems or having an accident. Etiology \200 Genetic: both genetic and environmental factors appear to play a role. The predisposition towards overly interpreting situations as dangerous may be genetic, and some commentators suggest an ethological factor involving an evolutionarily determined vulnerab ility to unfamiliar territory. First-degree relatives also have an increased prevalence of other anxiety and related disorders (e.g. panic disorder, social phobia), alcohol misuse, a nd depressive disorders. Psychoanalytical: transformed by displacement into phobic symptoms . Learning theory: unconscious con \202 icts are repressed and may be conditioned fear responses lead to learned avoidance. Comorbidity Panic disorder, depressive disorder, other anxiety and related disorders (e.g. 55% also have social phobia), alcohol and substance misuse. Differential diagnosis Other anxiety and related disorders (esp. generalized anxiety disord er, social phobia, OCD), depressive disorders, secondary avoidance due to delusional ideas in psychotic disorders. Management \200 Pharmacological short-term use only (may reinforce avoidance) \200\224most evidence for alp razolam/clonazepam. Psychological Behavioral methods: exposure techniques (focused on parti cular situations or places), relaxation training, and anxiety management. Cognitive methods : teaching about bodily responses associated with anxiety/education about panic attacks, mo di \201 cation of thinking errors. Antidepressants: as for panic disorder. BDZs 09_Semple_Chap09.indd 364 12/7/2012 3:34:07 PM AGORAPHOBIA 365 1 Literally \200\230fear of the market place \200\231 (Greek). 2 Whether or not agoraphobi a differs from panic disorder in neurobiology or simply represents a more severe form of pa nic disorder remains controversial. The similarities of epidemiology, genet- ics, environme ntal precipitants, and effective treatments are hard to ignore. NCS-R data (2006) suggest t hat pure agoraphobia does occur, but it is rarer than earlier epidemiological studies would suggest (e.g. the ECS) with a lifetime prevalence of 1.3% and 4:5 = 2:3. 09_Semple_Chap09.indd 365 12/7/2012 3:34:08 PM CHAPTER 9 Anxiety and stress-related disorders 366 Simple or speci \201 c phobias Essence Recurring excessive and unreasonable psychological or autonomic symp- toms of anxiety, in the (anticipated) presence of a speci \201 c feared object or situation (see Box 9.3 for glossary) leading, whenever possible, to avoid- ance. DSM-IV distinguishes 5 subtypes: animals, aspects of the natural envir onment, blood/injec tion/injury, situational, and \200\230other \200\231. Epidemiology Prevalence: (NCS-R) lifetime 12.5%, 12mths 8.7%, 6mths (ECA) 4.5 \200\22311.9% ; 4:5 (all) = 1:3; animal/situational phobias may be more common in 5; mean age of occurren ce is 15yrs: onset for animal phobias 77yrs, blood/ injection/injury 8yrs, situational pho bias 720yrs. Etiology \200 Genetic: both genetic and environmental factors play a role. MZ:DZ = 25.9%: 11.0%1 for animal phobia, situational phobia roughly equal suggesting stronger role for the environment. Psychoanalytical: manifest fear is the symbolic representation of an unconsci ous con \202 ict, which has been repressed and displaced into phobic symptoms. Learning th eory: situation, with learned avoidance (trigger to the conditioned response may be a remin der of the original situation). Observational and informational learning also appear to be important, and \200\230preparedness \200\231 theory (Marks)2 suggests that fear of certain objects may be evolutionarily adaptive (related to survival of the individual or species), selectively acquired, and dif \201 cult to extinguish. conditioned fear response related to a traumatic Comorbidity The lifetime risk for patients with speci \201 c phobias experiencing at least one other lifetime psychiatric disorder is reportedly over 80% (NCS), par- ticularly other anxiety disorders (panic, social phobia) and mood disorders (mania, depression, dysthymia) . However, rates of substance misuse are considerably less than in other anxiety disorders. Differential diagnosis Panic disorder (fear of having further panic attack), agoraphobia, s ocial phobia, hypochondriasis (fear of having a speci \201 c serious illness), OCD (avoida nce/fear of an object or situation due to obsessional thoughts, ideas, or ruminations), psy chosis (avoidance due to delusional idea of threat \200\224fears tend to be overly excessiv e). Management Psychological \200 Behavioral therapy to reduce the fear response, e.g. Wolpe \200\231s systematic desensitiza tion3 with relaxation and graded exposure (either imaginary or in vivo). : exposure is the treatment of choice: methods aim 09_Semple_Chap09.indd 366 12/7/2012 3:34:08 PM SIMPLE OR SPECIFIC PHOBIAS 367 Recent studies have utilized virtual environments (virtual reality exposure: VRE). Other te chniques: exposure), and modeling. Cognitive methods: education/anxiety management, coping skills/ strategies, and cognitive restructuring \200\224may enhance long-term outcomes. Pha rmacological fear/avoidance (with BDZs, e.g. diazepam) and allow the patient to engage in e xposure. May reduce the ef \201 cacy of behavior therapy by inhibiting anxiety during expo sure. B-blockers may be helpful, but reduce sympathetic arousal not subjective fear. Clear secondary depression may require an antidepressant. reciprocal inhibition, \202 ooding (not better than graded : generally not used, except in severe cases to reduce Course Without treatment, tends to run a chronic, recurrent course. However, individuals ma y not present unless life changes force them to confront the feared object or situation. 09_Semple_Chap09.indd 367 12/7/2012 3:34:08 PM CHAPTER 9 Anxiety and stress-related disorders 368 Box 9.3 Speci \201 c phobias \200\224selected glossary Accidents Animals Ants Automobiles Bees Birds Blood Bridges Cats Choking/being smothered Contamination, dirt, or infection Cre epy, crawly things Crossing streets Darkness Dentists Depth Doctors Dogs or rabies Everythi ng Feathers Flying Forests, at night Frogs Hair, fur, or animal skins Horses Hospitals Inje ctions Jumping Lightning and thunder Moths Needles Open high places Operations: surgical Pl aces: enclosed Railways/trains Rain Rats Reptiles Snakes Spiders Vomiting X-rays Dystychiphobia Zoophobia Myrmecophobia Amaxophobia, motorphobia Apiphobia, melissophobia Or nithophobia Haemophobia Gephyrophobia Felinophobia Anginaphobia, pnigophobia, pnigerophobia Molysomophobia, mysophobia Herpetophobia Agyrophobia Nyctophobia, scotophobia Dentophobia, odontophobia Bathophobia Iatrophobia Cynophobia Panophobia, panphobia, pamphobia Pteronoph obia Aviophobia Nyctohylophobia Batrachophobia Chaetophobia, trichophobia, doraphobia Equin ophobia, hippophobia Nosocomephobia Trypanophobia Catapedaphobia Brontophobia, karaunophobi a Mottephobia Aichmophobia, belonephobia Aeroacrophobia Tomophobia Claustrophobia Siderodro mophobia Ombrophobia, pluviophobia Zemmiphobia Herpetophobia Ophidiophobia Arachnophobia Em etophobia Radiophobia 09_Semple_Chap09.indd 368 12/7/2012 3:34:08 PM SIMPLE OR SPECIFIC PHOBIAS 369 1 Kendler KS, Neale MC, Kessler RC, et al. (1992) The genetic epidemiology of phobias in wo men. The interrelationship of agoraphobia, social phobia, situational phobia, and simple ph obia. Arch Gen Psychiat 49: 273 \200\22381. 2 Marks IM (1969) Fears and phobias. New York: Academic Press. 3 Wolpe J (1973) The practice of behavior therapy, 2nd edn. New York: Perga mon. 09_Semple_Chap09.indd 369 12/7/2012 3:34:08 PM CHAPTER 9 Anxiety and stress-related disorders 370 Social phobia Essence Symptoms of incapacitating anxiety (psychological and/or autonomic) are not s to de lusional or obsessive thoughts and are restricted to particular social situations, leading to a desire for escape or avoidance (which may reinforce the strongly held belief of social inadequacy). Epidemiology Lifetime rates vary from 2.4% (ECA) to 12.1% (NCS-R), 12-mth prevalence 6.8% ( NCS-R); 4 = 5 for those seeking treatment (however, commu- nity surveys suggest 4 > 5); bim odal distribution with peaks at 5yrs and between 11 \200\22315yrs (ECA) \200\224often patie nts do not present until they are in their 30s. Etiology Both genetic and environmental factors play a role. MZ:DZ = 24.4%:15.3%.1 The pred isposition towards overly interpreting situations as dangerous may be genetic, whereas indi vidual interpretations of social cues may be environmentally determined2 (i.e. the particul ar trigger for the conditioned fear response depends on the social situation in which \201 rst episode of anxiety experienced). Responses may be learned from observing parents. Imaging studies show increased activity in individuals with social anxiety in fear networks (prefrontal cortex, amygdala, hippocampus) during anxiety- provoking tasks.3 Response to a ntidepressants suggests there may be dys- regulation of 5-HT, NE, or DA systems. Symptoms/signs Somatic symptoms include blushing, trembling, dry mouth, perspiration when e xposed to the feared situation, with excessive fear (which is rec- ognized as such by the p atient) of humiliation, embarrassment, or others noticing how anxious they are. Individuals are often characteristically self- critical and perfectionistic. Avoidance of situations m ay lead to dif \201 culty in maintaining social/sexual relationships, educational problems (dif \201 culties in interactions with other students/oral presentations), or vocational prob- lems (work in less demanding jobs, well below their abilities). Thoughts of suicide a re relatively common. Comorbidity4 There is a high level of psychiatric comorbidity with the most common dis- ord ers including simple phobia, agoraphobia, panic disorder, generalized anxiety disorder, PTS D, depression/dysthymia, and substance misuse. Differential diagnosis Other anxiety and related disorders (esp. generalized anxiety disord er, agoraphobia, OCD), poor social skills, anxious/avoidant personality traits, depressive disorders, secondary avoidance due to delusional ideas in psy- chotic disorders, and substa nce misuse 09_Semple_Chap09.indd 370 12/7/2012 3:34:08 PM SOCIAL PHOBIA 371 Management \200 CBT, in either an individual or group setting (CBGT),5 Psychological: sho uld be considered as a \201 rst-line therapy (with SSRIs/MAOIs) and may be better at prev enting relapse. Components of this approach include relaxation training/anxiety management (for autonomic arousal), social skills training, integrated exposure methods (modeling and graded exposure), and cognitive restructuring. -blockers (e.g. atenolol) may reduce auton omic Pharmacological: arousal, particularly for \200\230speci \201 c social phobia \200 \231 (e.g. performance anxiety). For more generalized social anxiety, both SSRIs (e.g. esci talopram [licensed: 10mg/day initially; range 5 \200\22320mg/day], \202 uoxetine [unlicen sed], \202 uvoxamine [unlicensed], paroxetine [unlicensed], sertraline [licensed: 25mg/da y increased to 50mg/day after 1wk; max 200mg/day]), SNRIs (e.g. venlafaxine [licensed: 75mg / day]), and MAOIs (e.g. phenelzine [unlicensed]) are signi \201 cantly more effective. Ot her treatment possibilities include RIMAs (e.g. moclobemide [licensed: 300mg/day for 3 days , then 600mg/day in 2 divided doses]) or the addition of a BDZ (e.g. clonazepam, alprazolam ) or buspirone (to augment SSRI). Limited evidence for anticonvulsants (e.g. gabapentin, pr egabalin, levetiracetam, valproate [all unlicensed]). Course \200 \200 Without treatment, social phobia may be chronic lifelong condition. Course does not appear to be related to gender, age of onset, duration of illness, level of premorbid functioning, lifetime history of anxiety or depressive disorders. Extreme childhood shyness and behavio ral inhibition may be early manifestations of social phobia. With treatment, response rates may be up to 90%, especially with combined approaches. Medication best regarded as long-te rm, as relapse rates are high on discontinuation. 1 Kendler KS, Neale MC, Kessler RC, et al. (1992) The genetic epidemiology of phobias in wo men. The interrelationship of agoraphobia, social phobia, situational phobia, and simple ph obia. Arch Gen Psychiat 49: 273 \200\22381. 2 Rapee RM, Heimberg RG (1997) A cognitive-beha vioral model of anxiety in social phobia. Behav Res Ther 35: 741 \200\22356. 3 Stein MB, Go ldin PR, Sareen J, et al. (2002) Increased amygdala activation to angry and contemp- tuous faces in generalized social phobia. Arch Gen Psychiat 59: 1027 \200\22334. 4 Schneier FR, J ohnson J, Hornig CD, et al. (1992) Social phobia. Comorbidity and morbidity in an epidemiol ogic sample. Arch Gen Psychiat 49: 282 \200\2238. 5 Heimberg RG, Becker RE (2002) Cognitive -behavior group therapy [CBGT] for social phobia: basic mechanisms and clinical strategies. New York: Guildford Press. 09_Semple_Chap09.indd 371 12/7/2012 3:34:08 PM CHAPTER 9 Anxiety and stress-related disorders 372 Generalized anxiety disorder (GAD) Essence \200\230Excessive worry \200\231 (generalized free- \202 oating persistent anxiet y) and feelings of apprehension about everyday events/problems, with symptoms of mus- cle a nd psychic tension, causing signi \201 cant distress/functional impairment. Symptoms/signs See Box 9.4. Epidemiology Prevalence: 6mths (ECA) 2.5 \200\2236.4%, 12mths (NCS-R) 3.1%, lifetime (NCS-R ) 5.7%; lowest in 18 \200\22329yrs (4.1%) and 60+yrs (3.7%); highest 45 \200\22359yrs (7.7% ); 5>4 esp. early onset (associated with childhood fears and marital/sexual disturbance); l ater onset often after a stressful event; single (730% never marry); unemployed. Etiology (triple vulnerability model)1 \200 Generalized biological vulnerability: \200 \200 Genetic Neurobiological norepinephrine system: diminished autonomic nervous system responsi veness (? down-regulation of A 2 receptors); HPA axis: loss of regulatory control of cortis ol (71/3 of GAD patients show reduced cortisol suppression using the dexamethasone suppress ion test [DMST]); amygdala and stria terminalis \200\224possible sustained or repeated acti vation by CRF due to stress; septohippocampal ( \200\230behavioral inhibition \200\231) sys tem: sustained activation moderated by ascending 5-HT and NE systems; BDZ-GABA system: redu ced expression of peripheral BDZ receptors due to high cortisol levels; other neurotransmit ter systems: dysregulation of 5-HT systems, cholecystokinin (CCK-4 and CCK-8S). \200\224modest role, shared heritability with depression. \200\224human studies limited. Animal work implicates Generalized psychological vulnerability: \200 Diminished sense of control primary caregivers, leading to intolerance of uncertainty. Pare nting perceived control over events. Speci \201 c psychological vulnerability: early paren tal death, rape, war) and dysfunctional marital/family relationships. \200\224trauma or insecure attachment to \200\224overprotective or lacking warmth, leading to low stressful life events \200\224trauma (e.g. Comorbidity Other anxiety disorders (simple phobias, social phobia, panic disorder), depres sion/dysthymia, alcohol and drug problems, other \200\230physical \200\231 condi- tions (e .g. IBS, HVS, atypical chest pain). 09_Semple_Chap09.indd 372 12/7/2012 3:34:08 PM GENERALIZED ANXIETY DISORDER 373 Box 9.4 Symptoms of GAD (present most days for at least 6mths) \200 DSM-IV: \200 \200 \200 \200 \200 \200 ICD-10: \200 at least 3 (or 1 in children) out of: restlessness or feeling keyed up or on edge; easy fat iguability; concentration dif \201 culties or \200\230mind going blank \200\231; irritabi lity; muscle tension; sleep disturbance. at least 4 (with at least 1 from \200\230autonomic arousal \200\231) out of: Symptoms of autonomic arousal trembling/shaking; dry mouth. \200\230Physical \200\231 symp toms pain/discomfort; nausea/abdominal distress. Mental state symptoms headed; derealizatio n/depersonalization; fear of losing control, \200\230going crazy \200\231, passing out, dy ing. General symptoms Symptoms of tension inability to relax; feeling keyed up, on edge, or mentally tense; a sensation of a lump in the throat or dif \201 culty swallowing. Other C oncentration dif \201 culties/ \200\230mind going blank \200\231 anxiety; persistent irrit ability; dif \201 culty getting to sleep due to worrying. \200\224palpitations/tachycardia; sweating; \200\224breathing dif \201 culties; choking sensation; chest \200\224feeling dizzy, unsteady, faint or light- \200 \200\224hot \202 ushes/cold chills; numbness or tingling. \200\224muscle tension/aches and pains; restlessness/ \200 \200\224exaggerated responses to minor surprises/being startled. \200\224due to worry or Differential diagnosis \200\230Normal worries \200\231, depression, mixed anxiety/depressi on, other anxiety disorders (the anxiety is more focused), drug and alcohol problems, medi- cal conditions (see Box 9.5), side-effects of prescribed medications (see Box 9.6). Management \200 Psychological: (lack of situational triggers); some evidence for CBT2 com bining behavioral methods (treat avoidance by exposure, use of relaxation and control of hy perventilation) and cognitive methods (teaching about bodily responses related to anxiety/e ducation about panic attacks, modi \201 cation of thinking errors). Pharmacological: \200 \200 \200 generally less effective than in the other anxiety disorders directed towards predominant anxiety symptoms: \200\224buspirone3 (bene \201 cial effects may take 2 \200\2234wks); \200\224BDZs2 (e.g. lorazepam, diazepam); \200\224TCAs (unlicensed \200\224imipramine, psychic symptoms somatic symptoms depressive symptoms clomipramine), trazodone (licensed 75 \200\223300mg/day), SNRIs (licensed \200\224duloxetine 30 \200\22360mg/day, venlafaxine 75 \200\223225mg/day), SSRIs2 (licensed \200\224escitalopram 10 \200\22320mg/day, paroxetine 20 \200\22350mg/ day); 09_Semple_Chap09.indd 373 12/7/2012 3:34:08 PM CHAPTER 9 Anxiety and stress-related disorders 374 or autonomic symptoms \200\224B-blockers (e.g. cardiovascular symptoms atenolol); other licensed treatments pregabalin (start 150mg/day; m ax 600mg/day; in divided doses). Physical: psychosurgery (very rare) \200\224for severe/intractable anxiety. Course Chronic and disabling, prognosis generally poor, remission rates low (730% after 3yr s, with treatment); 6-yr outcome \200\22468% mild residual symptoms, 9% severe persistent i mpairment. Often comorbidity becomes more sig- ni \201 cant (esp. alcohol misuse) and this worsens the prognosis. Box 9.5 Medical conditions associated with anxiety-like symptoms \200 \200 \200 \200 : arrhythmias, IHD, mitral valve disease, cardiac failure. CVS Respiratory Neurological Endocrine phaeochromocytoma. Miscellaneous : asthma, COPD, HVS, PE, hypoxia. : TLE, vestibular nerve disease. : hyperthyroidism, hypoparathyroidism, hypoglycaemia, : anemia, porphyria, SLE, carcinoid tumor, pellagra. Box 9.6 Prescribed medications causing anxiety-like symptoms \200 \200 \200 CVS Respiratory CNS agents, antidepressants, antipsychotics, disul \201 ram reactions, wit hdrawal from BDZs and other sedatives. Miscellaneous : antihypertensives, anti-arrhythmics. : bronchodilators, A 1/B-adrenergic agonists. : anesthetics, anticholinergics, anticonvulsants, anti-Parkinsonian : levothyroxine, NSAIDs, antibiotics, chemotherapy. 09_Semple_Chap09.indd 374 12/7/2012 3:34:08 PM GENERALIZED ANXIETY DISORDER 375 1 Suarez L, Bennett SM, Goldstein CM, et al. (2008) Understanding anxiety disorders from a \200\230 triple vulnerability \200\231 framework. In: Antony MM and Stein MB, eds, Handboo k of anxiety and anxiety disor- ders. New York: Oxford University Press. 2 NICE recommends SSRIs as \201 rst-line treatment (+CBT) and does not recommend BDZs for more than 2 \200 \2234wks. See: M http://www.nice.org.uk/nicemedia/live/13314/52599/52599.pdf 3 Buspirone sh ould be considered as an alternative to BDZs when sedative effects are unwanted (e.g. drive rs of vehicles, pilots, machine operators), in patients with a personal/family history of d rug misuse, or for those already taking other CNS depressants. 09_Semple_Chap09.indd 375 12/7/2012 3:34:09 PM CHAPTER 9 Anxiety and stress-related disorders 376 Obsessive \200\223compulsive disorder (OCD) Essence A common, chronic condition, often asso ciated with marked anxiety and depression, characterized by \200\230obsessions \200\231 (s ee b p. 101) and \200\230compul- sions \200\231 (see b p. 89). Obsessions/compulsions must cause distress or interfere with the person \200\231s social or individual functioning (us ually by wast- ing time), and should not be the result of another psychiatric disorder. At some point in the disorder, the person recognizes the symptoms to be excessive or unreasona ble. Content of obsessions/compulsions Checking (63%), washing (50%), contamination (45%), doubt ing (42%), bodily fears (36%), counting (36%), insistence on symmetry (31%), aggressive tho ughts (28%). Epidemiology Mean age: 20yrs, 70% onset before age 25yrs, 15% after age 35yrs, 5=4, prevale nce: 0.5 \200\2233% of general population. Etiology of OCD \200 Neurochemical: 5-HT1B, or 5-HT/DA interaction. Immunological: e.g. a gainst basal ganglia peptides \200\224as in Sydenham \200\231s chorea. Imaging: CT and MRI: hypermetabolism in orbitofrontal gyrus, basal ganglia (caudate nuclei), and cingulum that \200\230normalizes \200\231 following successful treatment (either pharmacological or psyc hological). Genetic: relatives affected, MZ: 50 \200\22380% DZ: 25%), no candidate genes as yet identi \201 ed, but polymorphisms of 5-HT1BB have been replicated. defective arousal system and/or inability to control Psychological: unpleasant internal states. Obsessions ar e conditioned (neutral) stimuli, associated with an anxiety-provoking event. Compulsions ar e learned (and reinforced) as they are a form of anxiety-reducing avoidance. Psychoanalytic al: to be the result of regression from oedipal stage to pre-genital anal \200\223erotic st age of development as a defense against aggressive or sexual (unconscious) impulses. Associ ated defenses: isolation, undoing, and reaction formation. Symptoms occur when these defens es fail to contain the anxiety. dysregulation of the 5-HT system (possibly involving cell-mediated autoimmune factors may be associated bilateral reduction in caudate size. PET/SPECT: suggested by family and twin studies (3 \200\2237% of \201 rst-degree Freud coined the term \200\230obsessional neurosis \200\231, thought Associations Avoidant, dependent, histrionic traits (740% of cases), anankastic/obses- sive \200\223compulsive traits (5 \200\22315%) prior to disorder. In schizophrenia, 5 \200\2234 5% of patients may present with symptoms of OCD (schizo-obsessives \200\224 poorer prognosi s). Sydenham \200\231s chorea (up to 70% of cases) and other basal ganglia disorders (e.g. Tourette \200\231s syndrome, post-encephalitic Parkinsonism). 09_Semple_Chap09.indd 376 12/7/2012 3:34:09 PM OBSESSIVE \200\223COMPULSIVE DISORDER 377 Comorbidity Depressive disorder (50 \200\22370%), alcohol- and drug-related disorders, soci al phobia, speci \201 c phobia, panic disorder, eating disorder, PTSD, tic disorder ( 40% in juvenile OCD) or Tourette \200\231s syndrome. Differential diagnosis \200\230Normal \200\231 (but recurrent) thoughts, worries, or habit s (do not cause dis- tress or functional impairment); anankastic PD/OCD; schizophrenia; pho - bias; depressive disorder; hypochondriasis; body dysmorphic disorder; trichotillomania. Management1 \200 Psychological CBT \200\224 \200 approach, including exposure and respo nse prevention (ERP). Behavioral therapy \200\224 response prevention useful in ritualistic behavior; thought stopping may help in ruminations; exposure techniques for obsessions. Co gnitive therapy \200\224 Psychotherapy \200\224supportive: of groups); psychoanalytical: no unequivocal evidence of effectiveness (insight-orientated psychotherapy may be useful in s ome patients). recommended by NICE, but essentially takes a behavioral \200 so far not proven effective. valuable (including family members, use Pharmacological: \200 Antidepressants \202 uoxetine (20 \200\22360mg/day), \202 uvoxamine (100 \200\223300mg/ day), sertraline (150mg/day), or paroxetine (40 \200\22360mg/day) should be considered \201 rst-line (no clear superiority of any one agent, high doses usually needed, at least 1 2wks for treatment response, long-term therapy). Clomipramine (e.g. 250 \200\223300mg) has speci \201 c anti-obsessional action (NICE second-line choice). Other (unlicensed) agents include citalopram (20 \200\22360mg/day; NICE recommended alone or in combination with clom ipramine), venlafaxine (225 \200\223300mg). Augmentative strategies: pimozide) \200\224esp. if psychotic features, tics, or schizotypal traits (less evidence for olanzapine, quetiapi ne, aripiprazole); buspirone/short- term clonazepam (not NICE recommended) \200\224if marke d anxiety. SSRIs (licensed): escitalopram (10 \200\22320mg/day), antipsychotic (risperidone, haloperidol, Physical: \200 ECT \200\224 Psychosurgery \200 intractable cases (i.e. treatment-resist ant: 2 antidepressants, 3 combination treatments, ECT, and behavioral therapy), where the p atient can give informed consent \200\224e.g. stereotactic cingulotomy (reported up to 65% success). In theory, disrupts the neuronal loop between the orbitofrontal cortex and the ba sal ganglia. Deep brain stimulation (DBS) (severe refractory cases). consider if patient suicidal or severely incapacitated. may be considered for severe, incap acitating, ef \201 cacy remains to be established