Full medical history (particularly liver disease, hematological problems, and bleeding diso rders)/full physical examination; check FBC, LFTs, baseline ECG, weight/height (BMI). Sodiu m valproate: tds), increase every few days or every week by 200 \200\223400mg/day according to response and side-effects, up to a maximum of 2500mg/ day, or until serum levels are 50 \200\223125mmol/L (see Table 8.4). Usual maintenance dose 1 \200\2232g/day. Valproic acid as semisodium valproate: start with 250mg tds (or up to 20mg/kg for acute manic episode) an d increase every few days or every week by 250 \200\223500mg/day to a maximum of 2000mg/day , or until serum levels are 50 \200\223125mmol/L (see Table 8.4). Usual maintenance dose 10 00 \200\2232000mg/day. Once the patient is stable, simplify regime. If GI upset is a proble m with sodium valproate, consider changing to enteric-coated, slow-release (Epilim Chrono ), or Depakote . If poor compliance is an issue, consider use of slow-release tablets. Onc e established, check FBC, LFTs, serum valproate level, and BMI every 6 months. start with a low, divided dose (e.g. 200mg bd or \200 \200 Points to note \200 There is no well-established correlation between serum concentrations and mood-stabilizing effects. Best advice is to use similar doses and serum levels that are considered therapeut ic for epilepsy. Closer clinical monitoring for side-effects may be necessary for patients who cannot reliably report early signs. 08_Semple_Chap08.indd 343 12/7/2012 6:52:40 PM CHAPTER 8 Bipolar illness 344 Table 8.4 Valproate/valproic acid preparations (UK) Preparation Active agent Available strengths Depakote Valproic acid T 250/500mg Convulex Valproic acid C 150/300/500mg Sodium valproate (generic)/ Orlept Sodium valproate T 100/200/500mg L 200mg/5mL Epilim Sodium valproate T 100/200/500mg L 200mg/5mL Epilim Chrono (MR) Sodium valproate 200/300/500mg Epilim Chronosphere (MR granules) Sodium valproate 50/100/250/500 750/1000mg sachets Episenta (MR) Sodium valproate C 150/300mg Granules 500mg/1g Epilim intravenous Sodium valproate IV 400mg powder with 4mL water ampoule Episenta Sodium valproate IV 100mg/mL 3mL ampoule Key T: tablet; C: capsule; L: liquid 08_Semple_Chap08.indd 344 12/7/2012 6:52:40 PM This page intentionally left blank CHAPTER 8 Bipolar illness 346 Carbamazepine Psychiatric indications \200 Acute mania (less effective than lithium/equivalent ef \201 cacy to antipsychotics) \200 \224alone or in combination with lithium \200\224see b p. 326. Acute depressive episode (in bipolar affective disorder) \200\224alone or in combination with lithium \200\224see b p. 328. Prophylaxis of bipolar affective disorder \200\224data limited \200\224see b p. 330. Mode of action Uncertain. Modulates sodium and calcium ion channels, receptor-media- tion o f GABA and glutamine, and various intracellular signaling pathways. Pharmacokinetics Carbamazepine is available in a variety of forms (solutions, suspensions, syrups, and chewable or slow-release formulations), all with similar bioavailability. Peak plasma concentrations between 4 \200\2238hrs (usually), may be as late as 26hrs. Plasma hal f-life 18 \200\22355hrs. With long-term use, carbamazepine induces its own metabolism, decr easing the half-life to 5 \200\22326hrs (Box 8.10 and Table 8.5). Interactions \200 Carbamazepine decreases the plasma levels of many drugs metabolized by the liver, e.g. anti psychotics, BDZs (except clonazepam), TCAs, other anticonvulsants, hormonal contraceptives, thyroid hormones. Carbamazepine serum concentrations can be increased by certain drugs, e. g. erythromycin, calcium channel blockers (diltiazem and verapamil, but not nifedipine or n imodipine), SSRIs. Side-effects and toxicity \200 antidiuretic effects leading to hyponatraemia Unpredictabl e side-effects: (6 \200\22331%), probably more common in the elderly, sometimes developing many months after starting treatment; decrease in total and free thyroxine levels/increase in free cortisol levels (rarely clinically signi \201 cant). Idiosyncratic side-effects: f ailure, exfoliative dermatitis (e.g. Stevens \200\223Johnson syndrome), and pancreatitis (t hese side-effects usually occur within the \201 rst 3 \200\2236mths of treatment, rarely after longer periods). Note: routine blood monitoring does not reliably predict blood dyscr asias, hepatic failure, or exfoliative dermatitis \200\224patient education about early sym ptoms and signs is essential. Other rare side-effects: conduction problems, psychiatric sym ptoms (including occasional cases of mania and psychosis), and, extremely rarely, renal pro blems (failure, oliguria, haematuria, and proteinuria). Toxicity/overdose: Acute intoxicati on may present as marked irritability, stupor, or even coma. May be fatal in overdose (if > 6g ingested). Symptoms of overdose \200\224nystagmus, ophthalmoplegia, cerebellar/extra-pyr amidal agranulocytosis, aplastic anemia, hepatic systemic hypersensitivity reactions, cardiac early signs \200\224dizziness, ataxia, sedation, and diplopia. 08_Semple_Chap08.indd 346 12/7/2012 6:52:40 PM CARBAMAZEPINE 347 signs, impairment of consciousness, convulsions, respiratory depression, cardiac problems ( tachycardia, hypotension, arrhythmias/ conduction disturbances), GI upset, and other antich olinergic symptoms. Signi \201 cant overdose requires emergency medical management (i.e. c lose monitoring, symptomatic treatment, gastric lavage, and possible haemodialysis). Box 8.10 Treatment guidelines for carbamazepine \200 Full medical history (particularly liver disease, hematological problems, and bleeding diso rders); physical examination; check FBC, LFTs, U&Es, baseline ECG and weight/height (BMI). Start with a low, divided dose (e.g. 200 \200\223600mg/day in 2 \200\2234 divided doses), i ncrease every few days or every week by 200mg/day according to response and side-effects, u p to 800 \200\2231200mg/day, with slower increases thereafter as indicated, to a maximum of 2000mg/ day, or until serum levels are 4 \200\22315g/mL (trough level \200\224taken immedi ately prior to morning dose, and 5 days after dose change). See Table 8.5. Maintenance dose s are usually around 1000mg/day (range 200 \200\223 1600mg/day). Doses higher than 1600mg/d ay are not recommended. Check FBC, LFTs, and serum carbamazepine level every 2wks during \201 rst 2mths of treatment, then reduce monitoring to every 3mths, then every 6mths once w ell established (and monitor BMI). Once the patient is stable, simplify regimen and conside r use of slow-release preparation, to enhance compliance. Points to note Closer clinical monitoring for side-effects may be necessary for patients wh o cannot reliably report early signs. If carbamazepine is combined with lithium, there may be increased risk of developing acute confusional state. Closer monitoring is advisable and minimization of the use or dose of other medications (e.g. antipsychotics, anticholinergic s, BDZs) that may contribute to confusion. Table 8.5 Carbamazepine preparations Preparation Formulation Available strengths Tegretol Tablet (also Chewtabs ) 100/200/400mg Liquid 100mg/5mL Suppositories 125/250mg Tegretol Prolonged Release MR tablet 200/400mg Carbagen SR MR capsule 200/400mg Carbamazepine (generic) Tablet 100/200/400mg 08_Semple_Chap08.indd 347 12/7/2012 6:52:41 PM CHAPTER 8 Bipolar illness 348 Lamotrigine Psychiatric indications \200 Maintenance treatment of bipolar disorder to delay relapse (depression, mania, hypomania, m ixed episodes) \200\223 see b p. 330. May be more effective than other mood stabilizers in preventing depressive episodes in bipolar disorder. Mode of action Unknown. Inhibits voltage-gated Na channels and glutamate release. Also has weak inhibitory effect on 5-HT3 receptors. Pharmacokinetics Rapidly and completely absorbed after oral administration with negligible \201 rst-pass metabolism (absolute bioavailability is 98%). Bioavailability is not affect ed by food/drug administration. Peak plasma concentrations occur anywhere from 1 \200\2235h rs following. Half-life 24hrs, and time to steady state is 5 \200\2238 days. Drug is 55% pr otein bound (Box 8.11). Interactions \200 Certain medications have been shown to increase clearance of lamotrigine: carbamazepine (40 %), oxcarbazepine (30%), phenobarbital (40%), phenytoin (50%), ritonavir, methsuximide, rif ampicin, primidone, and certain estrogen-containing oral contraceptives. Valproate decrease s the clearance of lamotrigine (i.e. more than doubles the elimination half-life of lamotri gine), so reduced doses (no greater than 50% usual dose) of lamotrigine should be given. Side-effects and toxicity \200 dizziness, headache, blurred/double vision, Most common si de-effects: lack of co-ordination, sleepiness, nausea, vomiting, insomnia, and rash. Rare s ide-effects: rare incidence of multi-organ failure, various degrees of hepatic failure, ase ptic meningitis, movement disorders. Risk of rash: rash. Most are benign. A minority may be serious/life-threatening skin reactions requiring hospitalization, e.g. Stevens \200\223Jo hnson syndrome, toxic epidermal necrolysis, angioedema, and a rash associated with a number of systemic manifestations (i.e. fever, lymphadenopathy, facial swelling, hematological, a nd hepatological abnormalities): \200 10 \200\22314% of patients receiving lamotrigine will develop a Most likely to occur within \201 rst 2 \200\2238wks of treatment. Risk of rash more likel y when combined with valproate, exceeding recommended initial dose or recommended dose esca lation. Although most rashes resolve even with continuation of treatment, it is not possibl e to predict reliably which rashes will prove to be serious or life-threatening. Lamotrigin e should ordinarily be discontinued at \201 rst sign of rash, unless the rash is clearly not drug- related. Discontinuation of treatment may not prevent a rash from becoming life-t hreatening or permanently disabling/dis \201 guring. 08_Semple_Chap08.indd 348 12/7/2012 6:52:41 PM LAMOTRIGINE 349 It is recommended that lamotrigine not be restarted in patients who discontinued due to ras h associated with prior treatment (unless the potential bene \201 ts clearly outweigh the risks). Other rare side-effects: dyscrasias (neutropenia, leukopenia, anemia, thrombocytopenia, pan cytopenia, and, rarely, aplastic anemia and pure red cell aplasia), withdrawal seizures. serious hypersensitivity reactions, blood Box 8.11 Treatment guidelines for lamotrigine \200 \200 pregnancy test (in women of child-bearing age). Prior to starting: As monotherapy: start 25 mg/day for weeks 1 and 2. Increase to 50mg/ day for weeks 3 and 4. Increase by max 50 \200 \223100mg/day every 1 \200\2232wks thereafter. Usual dose 100 \200\223200mg/day in 1 \200 \2232 divided doses (max 500mg/day). See Table 8.6. With valproate: Increase to 25mg/day fo r weeks 3 and 4. Increase by 25 \200\22350mg/day every 1 \200\2232wks. Usual dose 100 \200 \223200mg/day in 1 \200\2232 divided doses. start 50mg/day for With carbamazepine and NOT t aking valproate: weeks 1 and 2. Then 50mg bd for weeks 3 and 4. Increase by max 100mg/day e very 1 \200\2232wks. Usual dose 200 \200\223400mg/day in 2 divided doses (up to 700mg/day s ometimes needed). If a patient has discontinued lamotrigine for a period of more than 5 hal f-lives (i.e. 5 days) it is recommended that initial dosing recommendations and guidelines be followed. Although there is no well-established correlation between serum concentrations and mood-stabilizing effects, antiepileptic therapeutic serum levels are 8 \200\22310mg/mL . start 25mg every other day for weeks 1 and 2. Monitoring \200 The value of monitoring plasma concentrations has not been established; however, due to dru g interactions, monitoring of concomitant drugs may be indicated, particularly during dosag e adjustments. Prior to treatment, the patient should be warned that a rash or other signs or symptoms of hypersensitivity (e.g. fever, lymphadenopathy, hives, painful sores in the m outh or around the eyes, or swelling of lips or tongue) warrant urgent medical assessment t o determine if lamotrigine should be discontinued (see side-effects and toxicity b p. 348). Table 8.6 Lamotrigine preparations Preparation Formulation Available strengths Lamictal Tablet 25/50/100/200mg Dispersible tablet 2/5/25/100mg Lamotrigine (generic) Tablet 25/50/100/200mg Dispersible tablet 5/25/100mg 08_Semple_Chap08.indd 349 12/7/2012 6:52:41 PM This page intentionally left blank 351 Chapter 9 Anxiety and stress-related disorders Introduction 352 Historical perspective 354 Hyperventilation syndrome (HVS) 356 Panic disor der 1: clinical features 358 Panic disorder 2: aetiological models 360 Panic disorder 3: ma nagement guidelines 362 Agoraphobia 364 Simple or speci \201 c phobias 366 Social phobia 3 70 Generalized anxiety disorder (GAD) 372 Obsessive \200\223compulsive disorder (OCD) 376 E xceptional stressors and traumatic events 380 Acute stress reaction (ICD-10) 382 Acute stre ss disorder (DSM-IV) 384 Adjustment disorders 386 Normal and abnormal grief reactions 388 P ost-traumatic stress disorder 1: diagnosis 390 Post-traumatic stress disorder 2: management 392 Depersonalization (derealization) syndrome 394 09_Semple_Chap09.indd 351 12/7/2012 3:34:06 PM CHAPTER 9 Anxiety and stress-related disorders 352 Introduction If schizophrenia is \200\230the heartland of psychiatry \200\231, then the ne urotic disor- ders surely make up much of the rest of the continent, in view of their preva lence in the general population (see Table 9.1) and the morbidity they cause. As unpopular as the term \200\230neurosis \200\231 has become (for a historical perspectiv e see b p. 354), it is still retained in the ICD-10 in the rubric \200\230neurotic, stress related, and somatoform disorders \200\231. DSM-IV has effec- tively carved up the neurose s into anxiety disorders, somatoform disor- ders, dissociative disorders, and adjustment di sorders. Here, we retain the use of \200\230neuroses \200\231 as shorthand for all these d isorders, but will use the subdivisions when talking about the particular disorders. We have all experienced anxiety symptoms, perhaps suffer from a par- ticular \200\230phobi a \200\231, or are a little bit obsessive about certain things, but to be clinically signi \201 cant, these problems must be severe enough to cause marked distress and/or substantia lly interfere with our day-to-day lives. Because of the recognizable quality of some of the symptoms of neurotic disorders, it may be helpful to divide them into three categories: The common neuroses \200 Anxiety/phobic disorders: anxiety disorder (GAD), speci \201 c (understandable) phobias (e.g. snakes, spiders), hypochondriasis, social phobia. Stress-rel ated disorders: post-traumatic stress disorder (PTSD). (OCD). Obsessive \200\223compulsive disorder e.g. panic disorder, agoraphobia, generalized e.g. acute stress reactions, adjustment disorder, The unusual neuroses (i.e. outwith \200\230normal \200\231 experience) \200 Anxiety/phobic disorders: feathers), dysmorphophobia. \200\230Hysterical \200\231 conversi on disorders. Dissociative/depersonalization \200\223derealization disorder. Somatoform dis orders. e.g. \200\230non-understandable \200\231 phobias (e.g. dirt, \200 \200 \200\230Culture-speci \201 c \200\231 disorders Seen only in certain populations. \200 \200 b p. 398). Chronic fatigue syndrome (CFS)/eating disorders (see Other \200\230culture-bound \200\231 disorders. This chapter deals with the anxiety, phobic, and stress-related disorders. Other disorders are covered in Chapter 19, b pp. 802 \200\22313 (conversion, somatization, CFS, hypochondri asis, dysmorphophobia), Chapter 10, b p. 398, and Chapter 22, b p. 914. Points to note \200 \200 Anxiety symptoms are common in the general population. Comorbidity is frequent (other neuro ses, depression, substance misuse, personality disorder). Anxiety disorders may often prese nt with physical symptoms. 09_Semple_Chap09.indd 352 12/7/2012 3:34:06 PM INTRODUCTION 353 Management will usually involve a combined approach (pharmacological and psychological). Table 9.1 Prevalence of psychiatric disorders in the general population Disorder Rate (%) Previous 6mths Lifetime Schizophrenia 0.9 1.5 Affective disorders 5.8 8.3 Substance abuse disorders 6.0 16.4 Anxiety disorders 8.9 14.6 Data derived from multiple community surveys. 09_Semple_Chap09.indd 353 12/7/2012 3:34:06 PM CHAPTER 9 Anxiety and stress-related disorders 354 Historical perspective The term \200\230neurosis \200\231 was coined by William Cullen in 1777, replacing \200\230ill- ness of the nerves \200\231 (coined by Robert Whytt in 1764 t o replace the old \200\230vapors \200\231), and meaning any disease of the nervous system without a known organic basis (which at the time also included epilepsy). Clinical descrip- tions of neurotic symptoms can be found in the works of Hippocrates. However, the \200 \230illness \200\231 later vanished under the cloak of both pagan and Christian beliefs, wi th typical symptoms attributed to the work of spirits, possession, or divine punishment. It did not resurface properly until the Renaissance (the 1500s) thanks (in part) to the witch craft trials, when doc- tors were called in to present diagnoses of known illnesses that co uld be mistaken for demonic possession (the \201 rst recorded \200\230medical defense \200\231!). Although there was much debate, the brain became the \201 nal resting place a s the organ most likely to be involved in the etiology of the condition. The history of the neuroses is tightly bound to the (re)discovery of hypnosis (formerly the remit of faith healing). The work of Franz-Anton Mesmer (1734 \200\2231815) \200\224mesmer ism \200\224and James Braid (1795 \200\2231860) \200\224 braidism \200\224was brought to Fr ance by Azam in 1859, coming to the atten- tion of Charcot, whose experiments with hysteric s would have a profound in \202 uence on one particular assistant \200\224Sigmund Freud. F reud \200\231s \201 rst paper, published in 1886, shortly after his return to Vienna, was of a case of \200\230traumatic hysteria \200\231 in a male patient. It was his Studies on hysteria, written with Josef Breuer and published in 1895, that provided the starting poin t of his subsequent major concepts of psychoanalytical theory \200\224including repression, psychic reality, and the subconscious. The idea of repression of trauma (out of consciousness) and the appear- ance of \200\230de fenses \200\231 was highly in \202 uential, with the neuroses regarded as ill- nesses of t he mind, needing psychotherapeutic treatment. Old arguments of emotional vs. physical facto rs resurfaced in the aftermath of the First World War, as some authorities found it dif \201 cult to attribute the illnesses seen in \201 t, healthy, young men (who had indisput ably experienced trau- matic events) to conversion hysteria or phobic neurosis. The encepha litis lethargicans epidemic in 1919, and the presence of numerous \200\230hysterical \200 \231 symptoms (e.g. convulsions, mutism, feelings of passion, obsessions/com- pulsions, spa sms) argued in favor of at least some of the neuroses having an organic basis. In the 1920s, Walter Cannon proposed the concept of the \200\230emergency reaction \200 \231, believing this \200\230 \201 ght-or- \202 ight \200\231 response was mediated by t he auto- nomic nervous system. He also noted that the physiological responses were too slow to account for feelings, and that some other \200\230neural mech- anism \200\231 must be at work. The dominance of the behaviorists in psychology relegated emotion to just another \200\230 way of acting \200\231 in a particular situation (albeit internally perceived). Although an over-simpli \201 cation, this led to the development of the \200\230conditioning theory \200\231 of anxiety. John Watson, the father of behav- iourism, claimed to have produced an animal phobia in an 11-mth-old boy, \200\230little Albert \200\231, by making a loud clan ging noise whilst the boy was play- ing with a rat. Watson proposed that neuroses arose out of traumatic learning situations and then persist to in \202 uence behavior throughout li fe. 09_Semple_Chap09.indd 354 12/7/2012 3:34:06 PM HISTORICAL PERSPECTIVE 355 This was adapted by the 1930s to include the concept of \200\230instrumental conditioning \200\231 (association of an emotionally arousing stimulus and a neu- tral response), and, i n the 1940s, Mowrer attempted to translate Freud \200\231s theory of anxiety neurosis into the language of learning theory: responses that reduce anxiety are learned \200\224sometime s these reinforced behaviors may be aberrant, unhelpful, or simply bizarre, and present as neuroses. \200\230Avoidance \200\231 was postulated as the behavior that was reinforced du e to successfully removing a \200\230negative reinforcer \200\231 (e.g. fear). These ideas led to the rational treatment of phobias with desensitization techniques. In the search for Cannon \200\231s neural mechanism, neurophysiologists used lesioning expe riments to identify the thalamus as a critical gateway for stimuli, and the hypothalamus as mediating the physiological response (via the HPA axis) \200\224the Cannon \200\223Bard th eory. Other theories emerged over the years (e.g. the Papez Circuit, 1937), and understandi ng the emotional life of the brain remains at the forefront of research (see The emotional brain by Joseph LeDoux, 1998). Inviting as psychological explanations appeared, the late 1950s also her- alded the arrival of the BDZs. \200\230Tranquilizers \200\231 (e.g. Miltown , Librium , Valium ) became the \200\230housewives \200\231 choice \200\231, effectively treating a multitude of neuro tic symptoms. Unfortunately, the indiscriminate use of these drugs led to them being demoni zed as causing dependence problems (despite evidence for their effectiveness when properly used). The advent of the antidepressants arti \201 cially separated neurotic depression fr om the other neuroses, but nonetheless some utility was also seen in treating the anxiety d isorders. A key study was the use of clomipramine in the treat- ment of OCD (see The boy wh o couldn \200\231t stop washing by Judith Rapoport, 1989). The fact that clomipramine was t he most serotonergic of the TCAs paved the way for the second-generation antidepressants (t he SSRIs) used in neuroses (previously thought only to be amenable to psychological approac hes). Brain imaging demonstrated underlying functional changes in OCD patients (in the frontal co rtex [left orbital gyrus] and bilateral caudate nuclei), which \200\230normalized \200\231 after successful treatment with medication (and interestingly with CBT techniques, althoug h this took longer). For many patients with panic attacks, structural and functional change s were found in the temporal lobes. These \201 ndings resonated with the long-held observ ation that neurotic symptoms (e.g. anxiety, panic, somatic symp- toms, depersonalization/de realization) were often reported in other \200\230organic \200\231 conditions (e.g. tempor al lobe epilepsy). Modern views are eclectic in their approach \200\224e.g. the biopsychosocial model (see b p . 245). For the neuroses, early environmental in \202 uences (including social factors lik e maternal deprivation) can alter the sensitivity of physiological stress responses in adul thood. Hence, the experience of stressors (psychological or physical) may lead (e.g. throug h the effects of stress hormones such as cortisol, and other neurophysiological mech- anism s) to alterations in the structure and/or function of the brain, which in turn manifest as clinical symptoms (i.e. behavioral and/or emotional change). 09_Semple_Chap09.indd 355 12/7/2012 3:34:06 PM CHAPTER 9 Anxiety and stress-related disorders 356 Hyperventilation syndrome (HVS)1 Essence Ventilation exceeds metabolic demands, leading to haemodynamic and chemical changes producing characteristic symptoms (dyspnoea, agita- tion, dizziness, atypical chest pain, tachypnoea, hyperpnoea, paraesthesias, and carpopedal spas m) usually in a young, otherwise healthy patient. HVS relatively common presentation; may b e mistaken for panic disorder. Considerable overlap, hence inclusion here: \200 50 \200\22360% of patients with panic disorder or agoraphobia have symptoms of HVS. 25 \200 \22335% of HVS patients have symptoms of panic disorder. It may also be confused with other organic diseases, particularly of the cardiorespiratory system, due to the physical symptoms manifest. Etiology Unknown, but certain stressors provoke an exaggerated respiratory response in some individuals (e.g. emotional distress, sodium lactate, caffeine, isoproterenol, cholecystok inin, and CO2). HVS patients tend to use accessory muscles to breathe, rather than the diap hragm, resulting in hyperin \202 ated lungs and perceived effort or dyspnoea when stressor s induce the need to take a deep breath. This leads to anxiety, and triggers further deep b reathing, setting up a vicious cycle. Epidemiology 5:4=7:1, usually presents between 15 and 55yrs, but can occur at any age (except infancy). Symptoms and signs \200 Cardiac not minutes; often relieved by exercise; GTN ineffective), ECG changes (prolonged Q T, ST depression or elevation, and T-wave inversion). Respiratory : hyperpnoea, tachypnoea, dyspnoea, wheeze (bronchospasm secondary to low PaCO2). Note: in chronic forms hyperventil ation may not be clinically apparent. (due to reduced CBF s to hypocapnia): dizziness, weak ness, CNS confusion, agitation, depersonalization, visual hallucinations, syncope or seizur e (rare), paraesthesias (usually upper limbs and bilateral), peri-oral numbness. GI dry mou th (due to mouth breathing and anxiety). Metabolic acute hypocalcaemia (signs: carpopedal s pasm, muscle twitching, +ve Chvostek and Trousseau signs, and prolonged QT interval), hypok alaemia (with generalized weakness), acute hypophosphataemia (may contribute to paraesthesi as and generalized weakness). : chest pain/angina (atypical of cardiac origin: may last hours, : bloating, belching, \202 atus, epigastric pressure (due to aerophagia), (due to electrolyte disturbance s to respiratory alkalosis): Differential diagnosis Extensive. Diagnosis of exclusion \200\224acute respiratory distress syndrome (ARDS), (venous) air embolism, asthma, atrial \201 brillation (AF), atrial 09_Semple_Chap09.indd 356 12/7/2012 3:34:07 PM HYPERVENTILATION SYNDROME 357 \202 utter, cardiomyopathy, chronic obstructive pulmonary disease (COPD), costochondritis , diabetic ketoacidosis (DKA), hyperthyroidism, metabolic acidosis, methaemoglobinaemia, MI , nasopharyngeal stenosis, panic (and other anxiety) disorder, pleural effusion, pneumonia, pneumothorax, pulmonary embolism (PE), smoke inhalation, CO poisoning, withdrawal syndrome s. Investigations \200 Unless there is a clear history of HVS, any \201 rst presentations of hyperventilation sh ould be referred for exclusion of serious underlying medical problems (see Differential dia gnosis). These investigations may include full physical, FBC, U&Es, TFTs, glucose, Ca2+, PO 4, pulse oximetry, arterial blood gas (ABG) (in HVS: pH normal, PaCO2 and HCO3 low), toxico logy, ELISA d-dimer (PE), ECG, CXR, and possibly V/Q scan. Repeating these investigations a t later presentations should only be done if there are new clinical \201 ndings. Management Acute management If serious underlying pathology excluded, management includes: \200 \200 \200 Reassuring the patient. Alleviating severe anxiety (e.g. use of BDZs). Establishment of nor mal breathing pattern (instructing the patient to breathe more abdominally using the diaphr agm; physically compressing the upper chest and instructing the patient to exhale maximally to reduce hyperin \202 ation). Note: use of rebreathing techniques (e.g. into a paper bag) is no longer rec- ommended due to reports of signi \201 cant hypoxia and death. This form of rebreathing may be unsuccess ful anyway because very distressed patients have dif \201 culty complying with the techniq ue and because CO2 itself may be a chemical trigger for anxiety. Further management \200 Education: e.g. hyperventilation, relaxation, and breathing techniques ( \200\230provocatio n \200\231 should only be performed in this setting). Formal breathing retraining (usually provided by physiotherapists) is available in some centers. Beta-blockers and BDZs may be o f some use. Some success reported for use of antidepressants in preventing further episodes . If there is clear psychiatric morbidity (e.g. anxiety or depression), this should also be speci \201 cally addressed. 1 Formerly known as Da Costa syndrome. Other archaic terms include: cardiac neurasthenia, c ardiac neurosis, circulatory neurasthenia, disordered action of the heart (DAH), effort syn drome, hyperdynamic \200\223adrenergic circulatory state, hyperkinetic heart syndrome, irri table heart, neurocirculatory asthenia, soldier \200\231s heart, vasoregulatory asthenia. 09_Semple_Chap09.indd 357 12/7/2012 3:34:07 PM CHAPTER 9 Anxiety and stress-related disorders 358 Panic1 disorder 1: clinical features Essence \200 Panic attack: period of intense fear characterized by a constellation of symptoms (see Box 9.1) that develop rapidly, reach a peak of intensity in about 10min, and generally do not l ast longer than 20 \200\22330min (rarely over 1hr). Attacks may be either spontaneous ( \200\230out of the blue \200\231) or situational (usually where attacks have occurred previ ously). Sometimes attacks may occur during sleep (nocturnal panic attacks), and rarely, phy siological symptoms of anxiety may occur without the psychological component (non-fearful p anic attacks). :2 Recurrent panic attacks, which are not s to substance Panic disorder misu se, medical conditions, or another psychiatric disorder. Frequency of occurrence may vary f rom many attacks a day to only a few a year. Usually a persistent worry about having anothe r attack or consequences of the attack (which may lead to phobic avoidance of places or sit uations \200\224see b p. 364), and signi \201 cant behavioral changes related to attack. 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 