The term ‘anxiety disorder’ encompasses a variety of complaints which can either exist on their own or in conjunction with another psychiatric or physical illness. Symptoms of anxiety vary but generally present with a combination of psychological, physical and behavioural symptoms (Fig. 28.2). Some of these symptoms are common to many anxiety disorders while others are distinctive to a particular disorder. Anxiety disorders are broadly divided into generalised anxiety disorder (GAD), panic disorder, social phobia, specific phobias, post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD), see Table 28.1. Patient testimonials are presented in Box 28.1. Approximately two-thirds of sufferers of an anxiety disorder will have another psychiatric illness. This is most commonly depression and often successful treatment of an underlying depression will significantly improve the symptoms of anxiety. Many patients will also present with more than one anxiety disorder at the same time which can further complicate treatment. Anxiety disorders are the most commonly reported mental illness and as a whole have a lifetime prevalence of 21% (Baldwin et al., 2005) with specific phobias the most commonly reported.

Fig. 28.2 The symptoms of anxiety.

Table 28.1 A brief description of the common anxiety disorders

Symptoms common to all anxiety disorders	Fear or worry, sleep disturbances, concentration problems, dry mouth, sweating, palpitations, GI discomfort, restlessness, shortness of breath, avoidance behaviour
Generalised anxiety disorder (GAD)	Persistent (free floating), excessive and inappropriate anxiety on most days for at least 6 months. The anxiety is not restricted to a specific situation
Panic disorder (with or without agoraphobia)	Recurrent, unexplained surges of severe anxiety (panic attack). Most patients develop a fear of repeat attacks or the implications of an attack. Often seen in agoraphobia (fear in places or situations from which escape might be difficult)
Social phobia (or social anxiety disorder)	A marked, persistent and unreasonable fear of being observed, embarrassed or humiliated in a social or performance situation (e.g. public speaking or eating in front of others)
Specific phobia	Marked and persistent fear that is excessive or unrealistic, precipitated by the presence (or anticipation) of a specific object or situation (e.g. flying, spiders). Sufferers avoid the feared object/subject or endure it with intense anxiety
Post-traumatic stress disorder (PTSD)	Can occur after an exposure to a traumatic event which involved actual or threatened death, or serious injury or threats to the physical integrity of self or others. The person responds with intense fear, helplessness or horror. Sufferers can re-experience symptoms (flashbacks) and avoid situations associated with the trauma. Usually occurs within 6 months of the traumatic event
Obsessive-compulsive disorder (OCD)	Persistent thoughts, impulses or images (obsessions) that are intrusive and cause distress. The person attempts to get rid of these obsessions by completing repetitive time-consuming purposeful behaviours or actions (compulsions). Common obsessions include contamination while the compulsion may be repetitive washing or cleaning

Box 28.1 Patient testimonies (NICE, 2005a,b)

Symptoms described by a sufferer of post-traumatic stress disorder:

I would feel angry at the way the crash happened and that there was nothing I could do to stop it or help. I was physically exhausted, but was finding it hard to sleep. As soon as the bedroom light went out at night a light would come on in my head and all I could do was lie there and think. When I would eventually fall asleep, I would wake up with nightmares of the crash. I could not get away from it. It was all I could think about in the day and all I would dream about at night.

Thoughts from a sufferer of obsessive-compulsive disorder:

I’ve just arrived home from work. Tired and tense, I’m convinced my hands are contaminated with some hazardous substance and my primary concern now is to ensure that I don’t spread that contamination to anything that I, or others, may subsequently touch. I will wash my hands, but first I will need to put a hand in my pocket to get my door keys, contaminating these, the pocket’s other contents, and everything else I touch on my way to the sink. It will be late evening before I will have completed the whole decontamination ritual.

A slow recovery described by a post-traumatic stress disorder and panic attack sufferer:

Slowly I gained ground and as each new insight came I was able to see my symptoms diminish. The panic attacks tapered off, the intensity of the flashbacks dwindled, and my irritable bowel began to loosen some of its hold on me. I was able to breathe again.

For all anxiety disorders together the overall female to male ratio is 2:1. The age of onset of most anxiety disorders is in young adulthood (20s and 30s), although the maximum prevalence of generalised anxiety and agoraphobia in the general population is in the 50–64 year age group.

Pathophysiology

Anxiety occurs when there is a disturbance of the arousal systems in the brain. Arousal is maintained by at least three interconnected systems: a general arousal system, an ‘emotional’ arousal system and an endocrine/autonomic arousal system (Fig. 28.3). The general arousal system, mediated by the brainstem reticular formation, thalamic nuclei and basal forebrain bundle, serves to link the cerebral cortex with incoming sensory stimuli and provides a tonic influence on cortical reactivity or alertness. Excessive activity in this system, due to internal or external stresses, can lead to a state of hyperarousal as seen in anxiety. Emotional aspects of arousal, such as fear and anxiety, are contributed by the limbic system which also serves to focus attention on selected aspects of the environment. There is evidence that increased activity in certain limbic pathways is associated with anxiety and panic attacks.

Fig. 28.3 Diagram of arousal and sleep systems. Arousal systems receive environmental and internal stimuli, cause cortical activation and mediate motor, autonomic and endocrine responses to arousal. Reciprocally connected sleep systems generate slow-wave sleep (SWS) and rapid eye movement sleep (REMS). Either system can be excited or inhibited by cognitive activity generated in the cortex.

These arousal systems activate somatic responses to arousal, such as increased muscle tone, increased sympathetic activity and increased output of anterior and posterior pituitary hormones. Inappropriate increases in autonomic activity are often associated with anxiety states; the resulting symptoms (palpitations, sweating, tremor, etc.) may initiate a vicious circle that increases the anxiety.

Several neurotransmitters have been implicated in the arousal systems. Acetylcholine is the main transmitter maintaining general arousal but there is evidence that heightened emotional arousal is particularly associated with noradrenergic and serotonergic activity. Drugs which antagonise such activity have anxiolytic effects. In addition, the inhibitory neurotransmitter γ-aminobutyric acid (GABA) exerts an inhibitory control on other transmitter pathways and increased GABA activity may have a protective effect against excessive stress reactions. Many drugs which increase GABA activity, such as the benzodiazepines, are potent anxiolytics.

Aetiology and clinical manifestations

Anxiety is commonly precipitated by stress but vulnerability to stress appears to be linked to genetic factors such as trait anxiety. Many patients presenting for the first time with anxiety symptoms have a long history of high anxiety levels going back to childhood. Anxiety may also be induced by central stimulant drugs (caffeine, amphetamines), withdrawal from chronic use of central nervous system depressant drugs (alcohol, hypnotics, anxiolytics) and metabolic disturbances (hyperventilation, hypoglycaemia, thyrotoxicosis). It may form part of a depressive disorder and may occur in temporal lobe lesions and in rare hormone-secreting tumours such as phaeochromocytoma or carcinoid syndrome.

Apart from the psychological symptoms of apprehension and fear, somatic symptoms may be prominent in anxiety and include palpitations, chest pain, shortness of breath, dizziness, dysphagia, gastro-intestinal disturbances, loss of libido, headaches and tremor. Panic attacks are experienced as storms of increased autonomic activity combined with a fear of imminent death or loss of control. If panic becomes associated with a particular environment, commonly a crowded place with no easy escape route, the patient may actively avoid similar situations and eventually become agoraphobic. When anxiety is precipitated by a specific cause then behaviour can become altered to ensure the sufferer avoids the cause. This avoidance behaviour can maintain the often irrational fear and strengthen the desire to avoid the threat.

Investigations and differential diagnosis

In patients presenting with symptoms and clinical signs of anxiety, it is important to exclude organic causes such as thyrotoxicosis, excessive use of stimulant drugs such as caffeine and the possibility of alcoholism or withdrawal effects from benzodiazepines. However, unnecessary investigations should generally be avoided if possible. Extensive gastroenterological, cardiological and neurological tests may increase anxiety by reinforcing the patient’s fear of a serious underlying physical disease.

Treatment

Treatment for anxiety disorders often requires multiple approaches. The patient may need short-term treatment with an anxiolytic, such as a benzodiazepine, to help reduce the immediate symptoms combined with psychological therapies and an antidepressant for longer term treatment and prevention of symptoms returning.

Psychotherapy

Psychological therapies (talking therapies) are generally considered first-line treatments in all anxiety disorders because they may provide a longer lasting response and lower relapse rates than pharmacotherapy. Psychotherapy, however, is less available, more demanding and takes longer time to work than pharmacotherapy. If the patient is unable to tolerate the anxiety or associated distress, then medicines are often used before psychotherapy or while awaiting psychotherapy. The ideal treatment should be tailored to the individual and may involve a combination of both psychotherapy and pharmacotherapy. The type of treatment should depend on symptoms, type of anxiety disorder, speed of response required, long-term goals and patient preference.

The specific psychotherapy with the most supporting evidence in anxiety disorders is cognitive behavioural therapy (CBT). Cognitive behaviour therapy focuses on the ‘here and now’ and explores how the individual feels about themselves and others and how behaviour is related to these thoughts. Through individual therapy or group work the patient and therapist identify and question maladaptive thoughts and help develop an alternative perspective. Individual goals and strategies are developed and evaluated with patients encouraged to practise what they have learned between sessions. Therapy usually lasts for around 60–90 minutes every week for 8–16 weeks, or longer in more resistant cases. Cognitive behavioural therapists are usually health professionals such as mental health nurses, psychologists, general practitioners, social workers, counsellors or occupational therapists who have undertaken specific training and supervision.

In PTSD, CBT is trauma focused, with the therapist helping the patient confront their traumatic memory and people or objects associated with this trauma. At the same time, patients are taught skills to help them cope with the emotional or physical response of this trauma. One such skill includes relaxation training which may involve systematically relaxing major muscle groups in a way that decreases anxiety. Another psychotherapy sometimes recommended in PTSD is eye movement desensitisation and reprocessing (EMDR). This involves briefly recounting the trauma or objects associated with the trauma to the therapist who will then simultaneously initiate another stimulus, for example, moving a finger continuously in front of the patient’s eyes or hand tapping. Over time it enables the patient to focus on alternative thoughts when associations with the trauma occur. A single session of debriefing following a traumatic event is not thought effective to prevent PTSD and, therefore, not recommended.

In OCD, CBT includes exposure and response prevention (ERP). This involves the therapist and the patient repeatedly facing the fears, beginning with the easiest situations and progressing until all the fears have been faced. At the same time the person must not perform any rituals or checks.

Specific phobias are also almost exclusively treated using exposure techniques and most patients will respond to this treatment. Only a very few will require additional drug therapy.

Other psychotherapies, although occasionally tried, have a poorer evidence base than CBT and are, therefore, not usually recommended. Self-help is one alternative technique which is recommended (NICE, 2007) for GAD and panic disorder. It involves using materials either alone or in part under professional guidance to learn skills to help cope with the anxiety. The materials such as books, tapes or computer packages can be accessed at home and in the patients’ own time. Some self-help material, however, is of poor quality, so it is probably best used in those who have mild symptoms and who do not need more intensive treatments.

Pharmacotherapy

Benzodiazepines

Benzodiazepines are commonly prescribed to provide immediate relief of the symptoms of severe anxiety. A number of different benzodiazepines are available (Table 28.2). These drugs differ considerably in potency (equivalent dosage) and in rate of elimination but only slightly in clinical effects. All benzodiazepines have sedative/hypnotic, anxiolytic, amnesic, muscular relaxant and anticonvulsant actions with minor differences in the relative potency of these effects.

Table 28.2 Profile of selected benzodiazepines (Bazire, 2009; Taylor et al., 2009)

Pharmacokinetics

Most benzodiazepines are well absorbed and rapidly penetrate the brain, producing an effect within half an hour after oral administration. Rates of elimination vary; however, with elimination half-lives from 8 to 35 h (see Table 28.2). The drugs undergo hepatic metabolism via oxidation or conjugation and some form pharmacologically active metabolites with even longer elimination half-lives. Oxidation of benzodiazepines is decreased in the elderly, in patients with hepatic impairment and in the presence of some drugs, including alcohol. Benzodiazepines are metabolised through the cytochrome P450 3A4/3 enzyme system in the liver, so significant enzyme inducers (such as carbamazepine) may reduce levels while enzyme inhibitors (e.g. erythromycin) may increase levels (Bazire, 2009).

Mechanism of action

Most of the effects of benzodiazepines result from their interaction with specific binding sites associated with postsynaptic GABA_A receptors in the brain. All benzodiazepines bind to these sites, although with varying degrees of affinity, and potentiate the inhibitory actions of GABA at these sites. GABA is the most important inhibitory neurotransmitter in the central nervous system (CNS). Neuronal activity in the CNS is regulated by the balance between GABA inhibitory activity and excitatory neurotransmitters such as glutamate. If the balance swings towards more GABA activity, sedation, ataxia and amnesia occur. Conversely, when GABA is reduced arousal, anxiety and restlessness occur. GABA_A receptors are multimolecular complexes that control a chloride ion channel and contain specific binding sites for GABA, benzodiazepines and several other drugs, including many non-benzodiazepine hypnotics and some anticonvulsant drugs (Haefely, 1990) (Fig. 28.4). The various effects of benzodiazepines (hypnotic, anxiolytic, anticonvulsant, amnesic, myo-relaxant) result from GABA potentiation in specific brain sites and at different GABA_A receptor types_. There are multiple subtypes of GABA_A receptor which may contain different combinations of at least 17 subunits (including α_1–6, β_1–3, γ_1–3 and others) and the subtypes are differentially distributed in the brain (Christmas et al., 2008). Benzodiazepines bind to two or more subtypes and it appears that combination with α₂-containing subtypes mediates their anxiolytic effects and α₁-containing subtypes their sedative and amnesic effects. There is some evidence that patients with anxiety disorders have reduced numbers of benzodiazepine receptors in key brain areas that regulate anxiety responses (Roy-Byrne, 2005). Secondary suppression of noradrenergic and/or serotonergic and other excitatory systems may also be of importance in relation to the anxiolytic effects of benzodiazepines.

Fig. 28.4 Schematic diagram of the GABA_A receptor. This consists of five subunits arranged around a central chloride ion channel (one subunit has been removed in the diagram to reveal the ion channel, shown in the closed position). Some of the subunits have binding sites for benzodiazepines (B) and other hypnotics and anticonvulsants. Activation of the receptor by GABA opens the chloride channel, allowing chloride ions (Cl⁻) to enter the cell, resulting in hyperpolarisation (inhibition) of the neurone. Occupation of the benzodiazepine site, along with GABA, potentiates the inhibitory actions of GABA.

Role in treating anxiety

The benzodiazepines have been used for over 40 years in the treatment of anxiety and can provide rapid symptomatic relief from acute anxiety states. Concerns over dependence and tolerance restrict use to short-term use only. Many clinical trials have shown short-term efficacy in patients with anxiety disorders, although the efficacy shown is in part dependent on the year of publication of the study. Older randomised controlled trials appear to show a larger effect than more recent ones (Martin et al., 2007). Anxiolytic effects have also been reported in normal volunteers with high trait anxiety and in patients with anticipatory anxiety before surgery. However, in subjects with low trait anxiety and in non-stressful conditions, benzodiazepines may paradoxically increase anxiety and impair psychomotor performance.

Although useful for many anxiety disorders, benzodiazepines are not generally recommended for those with panic disorder as the long-term outcome is poor (NICE, 2007). Some patients report worse panic attacks after the benzodiazepines are stopped. Benzodiazepines are also useful at the start of SSRI treatment in OCD and as hypnotics in PTSD (NICE, 2005a,b). They should, however, be used at the lowest effective dose prescribed intermittently where possible and used for no longer than 2–4 weeks.

Choice of benzodiazepine in anxiety

The choice of benzodiazepine depends largely on pharmacokinetic characteristics. Potent benzodiazepines such as lorazepam and alprazolam (Table 28.2) have been widely used for anxiety disorders but are probably inappropriate. Both are rapidly eliminated and need to be taken several times a day. Declining blood concentrations may lead to interdose anxiety as the anxiolytic effect of each tablet wears off. The high potency of lorazepam (~10 times that of diazepam), and the fact that it is available only in 1 and 2.5 mg tablet strengths, has often led to excessive dosage. Similarly, alprazolam (~20 times more potent than diazepam) has often been used in excessive dosage, particularly in the USA. Such doses lead to adverse effects, a high probability of dependence and difficulties in withdrawal.

Box 28.2 Some common benzodiazepine withdrawal symptoms

Symptoms common to anxiety states	Symptoms relatively specific to benzodiazepine withdrawal
Anxiety, panicAgoraphobia	Perceptual distortions, sense of movement
Insomnia, nightmares	Depersonalisation, derealisation
Depression, dysphoria	Hallucinations
Excitability, restlessness	Distortion of body image
Poor memory and concentration	Tingling, numbness, altered sensation
Dizziness, light-headedness	Skin prickling (formication)
Weakness, ‘jelly legs’	Sensory hypersensitivity
Tremor	Muscle twitches, jerks
Muscle pain, stiffness	Tinnitus
Sweating, night sweats	Psychosis^a
Palpitations	Confusion, delirium^a
Blurred or double vision	Convulsions^a
Gastro-intestinal and urinary symptoms

a Usually only on rapid or abrupt withdrawal from high doses.

A slowly eliminated benzodiazepine such as diazepam is more appropriate in most cases. Diazepam has a rapid onset of action and its slow elimination ensures a steady blood concentration. Clonazepam, although long acting, is more potent than diazepam and in practice is often difficult to withdraw from. It is only indicated for epilepsy in the UK, but is commonly used as an anxiolytic.

Parenteral administration of lorazepam or diazepam may occasionally be indicated for severely agitated psychiatric patients.

Selective serotonin reuptake inhibitors

The selective serotonin reuptake inhibitors (SSRIs) have a broad anxiolytic effect and are considered the first drug options in GAD, panic disorder, social phobia, PTSD and OCD (NICE, 2005a,b, 2007; Baldwin et al., 2005). Individual SSRIs have varying licensed indications across the anxiety disorders but this does not necessarily mean others have no supporting evidence. Where more than one SSRI is licensed in a particular disorder it is not possible to conclude which SSRI would be more effective because of the lack of direct head to head trials. The SSRIs do differ in their interaction potential, side effect profile and ease of discontinuation. Initial worsening of symptoms is common when starting an SSRI in anxiety, so beginning with half the dose than that used in depression is recommended as is reassuring the patient that this is usually only experienced for the first few weeks of treatment. In view of these concerns, the NICE (2007) guidelines for GAD and panic disorder recommend that patients are reviewed every 2 weeks for the first 6 weeks of treatment to monitor for efficacy and tolerability.

Tricyclic antidepressants

Certain TCAs such as clomipramine, imipramine and amitriptyline are efficacious in some anxiety disorders. They are, however, associated with a greater burden of adverse reactions such as anticholinergic effects, hypotension and weight gain. Of particular concern is the TCAs’ cardiac toxicity in overdose which relegates their use to second line following the failure of an SSRI. They should be avoided in any patient at risk of suicide or those with an underlying cardiac disease. TCAs commonly cause sedation which occasionally can prove useful in anxiety disorders. Clomipramine may also be slightly more effective in OCD compared with SSRIs.

Monoamine-oxidase inhibitors

The monoamine-oxidase inhibitors (MAOIs) are rarely used in practice because of their potential interactions with other medicines and tyramine in the diet. Moclobemide is a reversible MAOI, so causes fewer problematic interactions. Phenelzine and moclobemide are occasionally used by specialists in social phobia following the failure of an SSRI. Phenelzine is also recommended as a third-line treatment option in PTSD (NICE, 2005b).

Other antidepressants

The selective and noradrenaline reuptake inhibitor (SNRI) venlafaxine has some evidence to support its use in almost all the anxiety disorders, but it is only licensed for use in GAD and social phobia at a dose of 75 mg/day in the extended release form. Discontinuation symptoms are common following venlafaxine withdrawal and can be experienced after missing a single dose. Patients prescribed venlafaxine should be reminded of the importance of a slow withdrawal (over at least 4 weeks) when discontinuation is necessary. Venlafaxine can increase blood pressure at higher doses and so is contraindicated in patients with a very high risk of cardiac ventricular arrhythmia or uncontrolled hypertension. Duloxetine, another SNRI, is also licensed in GAD and can similarly increase blood pressure.

Mirtazapine, an α₂-adrenoreceptor antagonist, is recommended as an option for PTSD if patients do not wish to participate in trauma focused CBT (NICE, 2005b). Mirtazapine has a lower incidence of nausea, vomiting and sexual dysfunction than the SSRIs but can commonly cause weight gain and sedation.

No other antidepressants are routinely recommended for anxiety disorders, although some such as agomelatine are under clinical trials in anxiety to investigate potential future uses. To reduce the risk of symptoms returning patients should be advised to continue the antidepressant for at least 6 months following improvement of symptoms in GAD and panic disorder and for 12 months in PTSD, OCD and social phobia (NICE, 2005a, 2007; Baldwin et al., 2005). Those with an enduring and recurrent illness, however, may continue for many years, depending on the risk of relapse and severity of symptoms.

For a complete review of the antidepressants, including adverse effects and interactions, see Chapter 29.

Other medications occasionally used in anxiety

Hydroxyzine, a sedating antihistamine, is licensed for the short-term treatment of anxiety in adults at a dose of 50–100 mg four times a day. The clinical evidence only supports its use in GAD (for up to 4 weeks) if sedation is required. NICE supports the use of a sedating antihistamine in the immediate management of GAD but state they should not be used in panic disorders (NICE, 2007).

Antipsychotics have limited evidence and a high side effect burden when used in anxiety disorders. The first-generation (typical) antipsychotics are associated with movement disorders such as akathisia and tardive dyskinesia and so are rarely used in anxiety. The second-generation (atypical) antipsychotics are less likely to cause movement disorders but can have other physical health concerns. The majority of the evidence only supports antipsychotics (specifically risperidone and quetiapine) in combination with an SSRI in OCD in those who have failed to respond to the SSRI alone. Olanzapine augmentation has also been used in PTSD and social phobia.

Pregabalin is licensed for GAD and has shown an anxiolytic effect over placebo after 1 week in adults or 2 weeks in the elderly (Montgomery et al., 2008). Two short-term studies (4 and 6 weeks) suggest that pregabalin 400–600 mg/day is as effective but better tolerated than venlafaxine 75 mg/day XL or lorazepam 6 mg/day. Pregabalin, however, commonly causes dizziness, somnolence and nausea and is more expensive than other medication options in GAD and should be limited to specialist use only after other treatments have failed.

Buspirone, a 5HT_1A partial agonist, is licensed for short-term use in anxiety. It is not a benzodiazepine and so does not treat or prevent benzodiazepine withdrawal problems. In GAD, buspirone and other azapirones are superior to placebo in short-term studies (4–9 weeks) but less effective or acceptable than benzodiazepines (Chessick et al., 2006). NICE have said the evidence for buspirone in GAD is equivocal and, therefore, presumably not recommended (NICE, 2007). There is no evidence supporting buspirone in other anxiety disorders.

Propranolol and oxprenolol are both licensed for anxiety symptoms but are probably only useful for physical symptoms such as palpitations, tremor, sweating and shortness of breath. β-Blockers do not have sufficient evidence to support their inclusion in NICE guidelines but intriguingly small pilot studies indicate that giving an immediate course of propranolol following a traumatic event may prevent emerging PTSD (Pitman et al., 2002; Vaiva et al., 2003).

An overview of the recommended drug treatments in anxiety is provided in Table 28.3.

Table 28.3 Overview of the recommended drug treatments in anxiety