The pharmacological management of anxiety disorders

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Stephen Bleakley MRPharmS, MCMHP Review in association with The pharmacological management of anxiety disorders Progress in Neurology and Psychiatry is running a series of articles on the major

1 Stephen Bleakley MRPharmS, MCMHP Review in association with The pharmacological management of anxiety disorders Progress in Neurology and Psychiatry is running a series of articles on the major psychiatric drug groups, produced in association with the College of Mental Health Pharmacists. In this article, Stephen Bleakley provides an overview of the main types of anxiety disorder and the efficacy and side-effects of the drugs recommended for the treatment of these disorders. 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. Anxiety generally presents with a combination of psychological, physical and behavioural symptoms. Some of these symptoms are common to many anxiety disorders while others are distinctive to a particular disorder. Anxiety disorders can be broadly divided into: generalised anxiety disorder (GAD), panic disorder, social phobia, specific phobias, post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD). A short description of the clinical features of each can be seen in Table 1. To meet the diagnosis of an anxiety disorder, the symptoms must be prolonged, cause significant distress and impair social or daily functioning. Approximately two-thirds of sufferers will have another psychiatric illness, which is most commonly depression. 1 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. In adults, anxiety disorders as a whole have a lifetime prevalence of 21 per cent, 1 with specific phobias being the most commonly reported. Treatment options National Institute for Health and Clinical Excellence (NICE) guidelines cover the treatment of panic disorders with or without agoraphobia, GAD, PTSD and OCD. 2-4 The British Association of Psychopharmacology (BAP) has also produced guidelines covering treatment options in all the major anxiety disorders. 1 In all anxiety disorders, psychological therapies are generally considered first-line treatment options because they provide a longer lasting response and lower relapse rates than pharmacotherapy. An extensive review of psychological therapies is beyond the scope of this article but readers are reminded that treatments based on cognitive behavioural therapy (CBT) have the most supporting evidence and should be actively recommended. If the patient is unable to tolerate the anxiety or associated distress, then medicines are often used before 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, patient preference and previous response or adverse reactions. Specific phobias are almost exclusively treated using psychotherapy approaches so will not be discussed further. Pharmacotherapy Table 2 provides an overview of the recommended drug treatments for the main types of anxiety disorder. Antidepressants are recommended for patients who prefer medication, are unable to commit or have not responded to psychological therapies. In addition, antidepressants are considered a first-line treatment option either alone or in combination with CBT in patients suffering from OCD with moderate or severe impairment. 4 The number needed to treat to see one benefit with antidepressants (NNT) is around five in PTSD and GAD, 5,6 while in childhood and adolescent anxiety disorders this increases to The response rate to antidepressants in anxiety is often lower and takes longer than that seen in depression. Initial worsening of symptoms can occur and high therapeutic doses are often required to improve response. 1 A detailed review of antidepressants including adverse reactions and interactions can be viewed in an earlier article in this CMHP series. 8 SSRIs The selective serotonin reuptake inhibitors (SSRIs) have a broad anxiolytic effect and are considered the Progress in Neurology and Psychiatry 15

2 Anxiety disorder All anxiety disorders Generalised anxiety disorder (GAD) Panic disorder (with or without agoraphobia) Lifetime prevalence Clinical features Fear or worry, sleep disturbances, concentration problems, dry mouth, sweating, palpitations, GI discomfort, restlessness, shortness of breath, avoidance behaviour, etc. 5.1% Persistent (free floating), excessive and inappropriate anxiety on most days for at least six months.the anxiety is not restricted to a specific situation 3.8% Recurrent, unexplained surges of severe anxiety (panic attacks). 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). first drug options in GAD, panic disorder, social phobia, PTSD and OCD. 1-4 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. 1,9 The SSRIs do differ in their interaction potential, side-effect profile and ease of discontinuation. 8 Initial worsening of symptoms is common when starting an SSRI in anxiety, so beginning with half the dose of that used in depression is recommended, as is reassuring the patient that this is usually only experienced for the first few weeks of treatment. The NICE guidelines for GAD and panic disorder recommend that patients are reviewed every two weeks for the first six weeks of treatment to monitor for efficacy and tolerability, in view of these concerns. 2 Social phobia (or social anxiety disorder) Specific phobia Post-traumatic stress disorder (PTSD) Obsessive compulsive disorder (OCD) 5.8% 13.2% Not established A marked, persistent and unreasonable fear of being observed, embarrassed or humiliated in a social or performance situation, eg public speaking or eating in front of others Marked and persistent fear that is excessive or unrealistic, precipitated by the presence (or anticipation) of a specific object or situation, eg flying, spiders. Sufferers avoid the feared object / subject or endure it with intense anxiety Can occur after an exposure to a traumatic event that 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 six months of the traumatic event 0.8% 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 involve repetitive washing or cleaning Table 1. Prevalence and clinical features of the main types of anxiety disorder 1 16 Progress in Neurology and Psychiatry Tricyclic antidepressants Certain tricyclic antidepressants (TCAs) clomipramine, imipramine and amitriptyline are efficacious in some anxiety disorders. 1 They are, however, associated with a greater burden of adverse reactions such as anticholinergic effects, hypotension and weight gain. Of particular concern is their cardiac toxicity in overdose, which relegates their use to second-line options 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. 1 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. 1 Phenelzine is also recommended by NICE as a third-line treatment option in PTSD. 3 Other antidepressants The serotonin-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 dosage of 75mg daily in the extended release (XL) form.

3 Generalised Panic disorder Social phobia Obsessive Post-traumatic anxiety disorder (social anxiety compulsive stress disorder (GAD) disorder) disorder (OCD) (PTSD) Immediate management/ Benzodiazepines Benzodiazepines Benzodiazepines Benzodiazepines Hypnotics may be short-term treatment (2-4 weeks only); (not recommended (2-4 weeks only) (only to counter considered for hydroxyzine by NICE) initial worsening of short-term use SSRI symptoms) in insomnia First-line pharmacotherapy* SSRI SSRI SSRI SSRI SSRI escitalopram citalopram escitalopram escitalopram paroxetine paroxetine escitalopram paroxetine fluoxetine sertraline sertraline paroxetine fluvoxamine paroxetine sertraline Other drug treatments buspirone clomipramine** moclobemide*** clomipramine amitriptyline*** with some supporting duloxetine imipramine** phenelzine*** augmentation with augmentation with evidence imipramine mirtazapine venlafaxine quetiapine or olanzapine or pregabalin*** moclobemide risperidone*** risperidone*** venlafaxine venlafaxine imipramine mirtazapine** phenelzine*** venlafaxine * The licensed SSRI is indicated but other SSRIs may also be beneficial; ** Unlicensed but recommended by NICE; *** Usually prescribed by mental health specialists only Table 2. Overview of the recommended drug treatments for the main types of anxiety disorder 1-4,21 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 four weeks) when discontinuation is necessary. 2,8 Venlafaxine can increase blood pressure at higher doses so is contraindicated in patients with a very high risk of cardiac ventricular arrhythmia or uncontrolled hypertension. Duloxetine, another SNRI, is also licensed for GAD and can similarly increase blood pressure. Mirtazapine, an alpha 2 -adrenoreceptor antagonist, is recommended by NICE as an option for PTSD if sufferers do not wish to participate in trauma-focused CBT. 3 Mirtazapine has a lower incidence of nausea, vomiting and sexual dysfunction than the SSRIs but is commonly associated with weight gain and sedation. No other antidepressants are routinely recommended for anxiety disorders. To reduce the risk of symptoms returning, patients should be advised to 18 Progress in Neurology and Psychiatry continue the antidepressant for at least six months following improvement of symptoms in GAD and panic disorder and for 12 months in PTSD, OCD and social phobia. 1-4 However, those with an enduring and recurrent illness may continue for many years, depending on the risk of relapse and severity of symptoms. Benzodiazepines Benzodiazepines enhance the effects of gammaaminobutyric acid (GABA) in the CNS. GABA is the most important inhibitory neurotransmitter in the 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. 10 Benzodiazepines bind to the GABA A benzodiazepine receptor and allosterically change the receptor

4 complex, which in turn increases the efficiency of GABA in opening the GABA A chloride channel. 10 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 led the Committee on the Safety of Medicines in 1988 to restrict their use to short-term only. Despite this guidance, in 2002, 30 per cent of prescriptions for benzodiazepines indicated long-term use, which is known to be associated with road traffic accidents, dependence, tolerance and a risk of falls in the elderly. 11 The message of short-term use was repeated in a Chief Medical Officer bulletin in 2004, 11 which recommended that benzodiazepines should be prescribed for just two to four weeks for relief of severe or disabling anxiety that is subjecting the patient to unacceptable distress. Guidelines from NICE further state that benzodiazepines are not recommended for those with panic disorder as the long-term outcome is poor. 2 Some patients, for example, reported worse panic attacks after the benzodiazepines were stopped. In practice, benzodiazepines do have a role for short-term use in GAD, social phobia, at the start of SSRI treatment in OCD and as hypnotics in PTSD. 1 They should, however, be used at the lowest effective dose, prescribed intermittently where possible and used for no longer than two to four weeks. Other medications occasionally used in anxiety Hydroxyzine, a sedating antihistamine, is licensed for the short-term treatment of anxiety in adults at a dosage of mg four times daily. The clinical evidence only supports its use in GAD (for up to four weeks) if sedation is required. 1,12 NICE supports the use of a sedating antihistamine in the immediate management of GAD but states they should not be used in panic disorders. 2 Antipsychotics have limited evidence and a high side-effect burden when used in anxiety disorders. 1 The first generation (typical) antipsychotics are associated with movement disorders such as akathisia and tardive dyskinesia so are rarely used in anxiety. The second generation (atypical) antipsychotics are less likely to cause movement disorders but are associated with other physical health concerns. An extensive review of antipsychotics was the subject of a previous article in this series. 13 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. 14 Olanzapine augmentation has also been used in PTSD and social phobia. 1 Table 3. Advice for patients Reassure the patient that active treatment is available and that sufferers do get better For long lasting treatment, psychotherapy must be sought and actively engaged in Initial worsening of symptoms is occasionally reported at the start of SSRI or SNRI treatment. Starting at half the normal dose and increasing gradually is recommended Antidepressant treatment is long term.treatment should continue for at least six months in GAD and panic disorder and 12 months in PTSD, social phobia and OCD after improvement of symptoms. Longer treatment will be needed in those with persistent or recurrent symptoms Benzodiazepines should be used intermittently where possible, at the lowest effective dose, and for no longer than two to four weeks Pregabalin is licensed for GAD and has shown an anxiolytic effect over placebo after one week in adults or two weeks in the elderly. 15,16 Two short-term studies (four and six weeks long) suggest that pregabalin mg daily is as effective but better tolerated than venlafaxine XL 75mg daily or lorazepam 6mg daily. 16,17 Pregabalin, however, is commonly associated with dizziness, somnolence and nausea and is more expensive than other medication options in GAD so perhaps should be limited to specialist use only after other treatments have failed. Buspirone, which is a 5HT 1A partial agonist, is licensed for short-term use in anxiety. It is not a benzodiazepine so does not treat or prevent benzodiazepine withdrawal problems. A Cochrane review on GAD found buspirone and other azapirones to be superior to placebo in short-term studies (four to nine weeks) but less effective or acceptable than benzodiazepines. 18 NICE states that the evidence for buspirone in GAD is equivocal and it is therefore, presumably, not recommended. 2 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. Beta-blockers do not have sufficient evidence to support their inclusion in the NICE guidelines but, intriguingly, small pilot studies indicate that giving an immediate course of propranolol following a traumatic event may prevent emerging PTSD. 19,20 Conclusion Clinicians are reminded to actively seek psychotherapy approaches when first treating an anxiety Progress in Neurology and Psychiatry 19

5 disorder. Pharmacotherapy has an important role either in conjunction with psychotherapy or as an alternative if appropriate. Drugs can provide immediate symptomatic relief, as with the benzodiazepines, or longer lasting remission, as with the antidepressants. If benzodiazepines are being considered, they should only be prescribed for intermittent, short courses to avoid the development of tolerance and dependence. Antidepressants such as the SSRIs can provide longer term control but may cause an initial worsening of symptoms and will usually require higher doses than those used in depression to be fully effective. Declaration of interest The author has received honoraria from Janssen-Cilag and Lundbeck. Stephen Bleakley is a Locality Lead Pharmacist Mental Health, Hampshire Partnership NHS Foundation Trust, and Registrar for the College of Mental Health Pharmacists References 1. Baldwin D,Anderson I, Nutt D, et al. Evidence-based guideline for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2005;19: National Institute for Health and Clinical Excellence.Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. Clinical Guidelines (2004) 3. National Institute for Health and Clinical Excellence. Post Traumatic Stress Disorder (PTSD) Clinical Guideline (2005) 4. National Institute for Health and Clinical Excellence. Obsessive Compulsive Disorder. Clinical Guideline (2005) 5.Kapczinski FFK,Silva de Lima M,dos Santos Souza JJSS,et al.antidepressants for generalized anxiety disorder. Cochrane Database of Systematic Reviews 2003, Issue 2.Art. No.: CD DOI: / CD Stein DJ, Ipser JC, Seedat S. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database of Systematic Reviews 2006, Issue 1.Art. No.: CD DOI: / CD pub2. 7. Ipser JC, Stein DJ, Hawkridge S, Hoppe L. Pharmacotherapy for anxiety disorders in children and adolescents.cochrane Database of Systematic Reviews 2009, Issue 3.Art.No.: CD DOI: / CD pub2 8. Bleakley S. Review of choice and use of antidepressants. Progress in Neurology and Psychiatry 2009;vol 13, issue 1: Soomro GM,Altman DG, Rajagopal S, Oakley Browne M. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD DOI: / CD pub3 10. Nutt D, Malizia A. New insights into the role of the GABA A -benzodiazepine receptor in psychiatric disorder. Br J Psychiatry 2001;179: Chief Medical Officer update Number 37.Patient safety.benzodiazepine warning. (2004) 12. Darcis T, Ferreri M, Natens J, et al.a multicentre double-blind placebo controlled study investigating the anxiolytic efficacy of hydroxyzine in patients with generalized anxiety. Hum Psychopharmacol Clin 2005;10: Parker C.Antipsychotics in the treatment of schizophrenia.progress in Neurology and Psychiatry 2009;Vol 13, issue 2: Ipser JC, Carey P, Dhansay Y, et al. Pharmacotherapy augmentation strategies in treatment-resistant anxiety disorders.cochrane Database of Systematic Reviews 2006, Issue 4.Art. No.: CD DOI: / CD pub2 15. Montgomery SA, Chatamra K, Pauer L, et al. Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder. Br J Psychiatry 2008;193: PandeA,Crockatt J,Feltner D,et al.pregabalin in generalized anxiety disorder: A placebo controlled trial. Am J Psychiatry 2003:160; Montgomery SA,Tobias K, Zornberg GL, et al. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder:a 6 week, multicenter, randomized, double blind, placebo controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry 2006; 67: Chessick CA,Allen MH,Thase ME, et al. Azapirones for generalized anxiety disorder. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD DOI: / CD Pitman R, Sanders K, Zusman R, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry 2002;51: Vaiva G, Ducrocq F, Jezequel K, et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry 2003;54: Taylor D, Paton C, Kapur S.The Maudsley Prescribing Guidelines 10th Edition. London: Informa Healthcare, 2009.

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