NPS News 65: Which treatment for what anxiety disorder?

• Starting and continuing antidepressants
• Limit benzodiazepine use
• Treating premenstrual dysphoric disorder
• Case study 60: Managing anxiety disorders
• Insert: Symptoms and differential diagnoses, psychological and non-drug therapies
• Reviewers

Up to 1 in 5 people presenting to primary care will experience symptoms of an anxiety disorder at some point in their life.[1] Psychological therapies should be the first choice for most anxiety disorders to control symptoms and improve functioning.[2] If these do not provide sufficient benefit and drug therapy is needed, an antidepressant may be added. In this NPS News, we discuss some general principles for managing anxiety disorders, including the role of psychological and drug therapies, with a focus on generalised anxiety disorder (GAD) and social anxiety disorder (also known as social phobia).

Anxiety disorders: diagnosis and role of psychological therapies

Anxiety symptoms may be primary or secondary to other physical or psychiatric disorders. Anxiety disorders are usually chronic conditions and may coexist with other disorders (e.g. anxiety, mood or substance use). Characterise all anxiety symptoms against criteria to ensure accurate diagnosis and effective therapy (see Table in pdf).[3,4]

Psychological therapies such as cognitive behavioural therapy (CBT) and non-drug strategies are first-line for most anxiety disorders (see Box in pdf).[2,3,5] Many people prefer psychological therapies to drug therapy. Subsidised psychological therapy is available with a GP referral to a psychologist[A] and a GP Mental Health Care Plan.[B][6,7] However, the use of psychological therapies may be limited by the availability of qualified practitioners, their time-consuming nature and the motivation or preferences of some patients.[2]

The benefits of psychological therapies for both GAD and generalised social anxiety disorder are maintained for ≥ 12 months after stopping therapy[1], and could be expected to continue for as long as people apply the skills learned. Up to 40% of patients relapse 6–12 months after stopping drug therapy.[1]

[A] Up to a maximum of 12 sessions per calendar year (review by the referring GP is required after the initial 6 sessions).

[B] GP Medicare items 2710, 2712, 2713.

Starting and continuing antidepressant therapy for GAD and generalised social anxiety disorder

If psychological and other non-drug therapies do not provide sufficient benefit or are unsuitable, an antidepressant may be added. Guidelines do not recommend starting with combined therapy (an antidepressant combined with psychological and other non-drug therapies) because there is no evidence that the combination is more effective than either an antidepressant or psychological and other non-drug therapies alone.[1,5] Not all antidepressants have been assessed for efficacy for all anxiety disorders, nor can efficacy be generalised across an antidepressant class (see Tables 1 and 2).[5] Consider the adverse effect profile and concomitant medicines before prescribing. Assess efficacy after at least 12 weeks therapy (in contrast to 6–8 weeks for major depression).

It appears that CBT or an antidepressant may be similarly effective for GAD or generalised social anxiety disorder.[1,3,5] Few trials have directly compared drug and psychological therapies (alone or in combination) and long-term comparative efficacy is unknown.[5] There is likely to be a significant placebo response: for example in a small (n = 265) 14 week trial, the response rate in generalised social anxiety disorder was 32% with placebo compared with 51% with fluoxetine, 52% with group CBT, 54% with group CBT + fluoxetine and 51% with group CBT + placebo.[8]

Which antidepressant for GAD?

Antidepressants are more effective than benzodiazepines for treating the uncontrollable worry associated with GAD and they do not produce tolerance or dependence.[1,3]

Most people presenting to primary care with GAD have comorbidities such as major depression or a substance use related disorder. Trials may not give an accurate estimate of the ‘real life’ effect of antidepressants for GAD because such patients are excluded. A meta-analysis of imipramine, paroxetine and venlafaxine (which included trials excluding people with comorbidities) found that about 5 people need to be treated for 1 person to benefit clinically. It also showed that similar numbers of people taking these antidepressants or placebo therapy withdrew because of adverse effects.[9] In practice the use of imipramine is limited by the risk of death in overdose and adverse effects.[1]

Antidepressants for social anxiety disorder: non-generalised and generalised

There is little evidence for antidepressants in non-generalised social anxiety disorder: beta-blockers (e.g. propranolol) can be used before the social event or performance.[1,3]

Short-term (12–24 weeks) trials in generalised social anxiety disorder show that escitalopram, fluvoxamine, paroxetine, sertraline and venlafaxine appear to be similarly effective but differ in their adverse effects.[10]

Long-term therapy with escitalopram, paroxetine or sertraline has been shown to prevent relapse in generalised social anxiety disorder.[5] Phenelzine (a non-selective MAOI) is effective but use is limited by its adverse effect profile (e.g. sedation, weight gain), significant interactions with many other drugs, and the need to avoid all foods containing tyramine (e.g. matured cheese).[3]

Table 1: Guideline recommendations for drug therapy for GAD and generalised social anxiety disorder[C][1,3,5,11]

Table 2: Prescribing antidepressants in Australia for GAD, generalised social anxiety disorder and premenstrual dysphoric disorder (PMDD)[2,12]

[C] TGA-approved indications for GAD, social anxiety disorder and PMDD are listed; refer to approved product information and the Schedule of Pharmaceutical Benefits for information about other indications.

Reserve benzodiazepine use to limited circumstances

In general, reserve benzodiazepine use to the short-term for people who have not responded to at least 2 therapies (e.g. psychological therapy, antidepressant).[1,5] Benzodiazepines may cause dependence — particularly in those with a history of dependence on alcohol and/or other drugs — and a withdrawal syndrome. Up to a third of people taking a benzodiazepine long-term have difficulty withdrawing or stopping.[1,3,5,13]

However, a benzodiazepine may be useful:

• For an acute exacerbation of GAD refractory to non-drug strategies and psychological therapies. Gradually reduce the benzodiazepine dose to zero within 6 weeks.[3]

• Before the social event or performance for people with non-generalised social anxiety disorder who cannot use propranolol (e.g. those with asthma).[3] However, adverse effects (e.g. sedation) may limit their use.[3]

The long-term use of benzodiazepines for GAD is controversial.[1,3,11] Consider only for people for whom non-drug strategies, psychological therapies and alternative drug therapies (e.g. SSRI) have failed to provide significant improvement.[3] Try to wean every 6–12 months by gradual dose reduction and increased focus on psychological therapy (to manage symptom exacerbation).[3]

For generalised social anxiety disorder, limit long-term benzodiazepines to people who have unsuccessfully trialled at least 2 antidepressants, and only for those with no history of alcohol and/or other drug abuse or depression (common co-morbidities).[1,3]

To use, or not to use: an antidepressant for premenstrual dysphoric disorder (PMDD)

Most women experience premenstrual symptoms, but only 3% to 8% meet the DSM-IV research criteria[E][14] for PMDD (also called severe premenstrual syndrome).[4,15,16] The cause is unknown, but it may be due to an interaction between normal cyclical ovarian activity and central nervous system transmitters, particularly serotonin.[17,18]

Antidepressants have not been directly compared with other drugs for PMDD (e.g. oral contraceptives). Uncertainties remain about the efficacy, tolerability and safety of long-term SSRI therapy because of a lack of long-term trials.

Start with non-drug strategies and lifestyle changes

PMDD is a chronic condition, with symptoms lasting possibly until menopause. The efficacy, adverse effects and cost of treatment are important considerations.

Start with non-drug strategies (e.g. CBT, relaxation training) and lifestyle changes (e.g. exercise)[17]: see the NPS RADAR review for details.[E][14]

Consider adding an SSRI for women who still have symptoms after 2–3 months of non-drug strategies and lifestyle changes.[16,17] Trials of oral contraceptives have conflicting results but they may be an option for women who have only physical symptoms.[15–17]

Continuous vs cyclic dosing for PMDD

Both continuous and cyclic (also called intermittent or luteal) dosing of SSRIs have shown similar efficacy.[18] Cyclic dosing is possible because symptoms only occur during the luteal phase, SSRIs have a rapid onset of action (1–2 days)[15] and gradual discontinuation is unnecessary[18] (see Table 3). Cyclic dosing is less expensive, reduces drug exposure and may be suitable for women who have regular cycles or are considering pregnancy. However, it is unclear how cyclic dosing influences the severity and frequency of adverse effects or potential drug interactions, and women need to keep track of their cycle so they know when to start and stop therapy.[19]

Table 3: Continuous and cyclic dosing of SSRIs for PMDD[2]

[E] See the NPS RADAR review Sertraline (Zoloft), fluoxetine (Lovan, Prozac) for premenstrual dysphoric disorder (PMDD) for details.

Expert reviewer

Philip Mitchell

Scientia Professor and Head School of Psychiatry University of New South Wales

Any correspondence regarding content should be directed to NPS. Declarations of conflicts of interest have been sought from all reviewers. The opinions expressed do not necessarily represent those of the reviewers.

Communications review group

Dr Graham Emblen, General Practitioner, Toowoomba

Dr James Best, General Practitioner, Sydney

Dr Guan Yeo, Clinical Education Consultant and General Practitioner, Berowra

A/Prof Nick Buckley, Consultant Clinical Pharmacologist and Toxicologist, University of New South Wales

Jan Donovan, Consumer Representative

Dr John Dowden, Editor, Australian Prescriber

Deborah Norton, QUM Pharmacist, West Vic DGP

Susan Parker, Pharmacist, Sydney

Dr Jane Robertson, Senior Lecturer, Discipline of Clinical Pharmacology University of Newcastle

Simone Rossi, Managing Editor, Australian Medicines Handbook

References

1. Canadian Psychiatric Association. Clinical practice guidelines: management of anxiety disorders. Can J Psychiatry 2006;51:1–92S.
2. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2009.
3. Psychotropic Writing Group. Therapeutic Guidelines: Psychotropic. Version 6 Updated March 2009 [eTG complete CD-ROM]. Melbourne: Therapeutic Guidelines Ltd, 2008.
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV-TR. 4th (text revision) ed. Washington, DC: American Psychiatric Association, 2000.
5. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology 2005;19:567–96.
6. Department of Health and Ageing. MBS Online: Medicare Benefits Schedule Canberra, 2009. (accessed 1 June 2009).
7. Department of Health and Ageing. Better Access to Mental Health Care. Canberra, 2009. (accessed 1 June 2009).
8. Davidson JRT, Foa EB, Huppert JD, et al. Fluoxetine, comprehensive cognitive behavioral therapy and placebo in generalised social phobia. Arch Gen Psychiatry 2004;61:1005–13.
9. Kapczinski FFK, Silva de Lima M, dos Santos Souza JJSS, et al. Antidepressants for generalized anxiety disorder. Cochrane Database Syst Rev 2003;2:CD003592.
10. Hansen RA, Gaynes BN, Gartlehner G, et al. Efficacy and tolerability of second-generation antidepressants in social anxiety disorder. International Clinical Psychopharmacology 2008;23:170–9.
11. National Institute for Health and Clinical Excellence. Anxiety (amended): management of anxiety (panic disorder, with or without agoraphobia, and generalized anxiety disorder) in adults in primary, secondary or community care.  NICE Clinical Guideline 22 (amended). London: NICE, 2007. (accessed 7 April 2009).
12. Department of Health and Ageing. PBS for Health Professionals. Canberra, 2009.(accessed 21 April 2009).
13. Anderson I. The new guidelines from the British Association for Psychopharmacology for anxiety disorders. Int J Psychiatry Clin Pract 2006;10 (Suppl. 3):10–7.
14. Rapkin AJ, Winer SA. The pharmacologic management of premenstrual dysphoric disorder. Expert Opin Pharmacother 2008;9:429–45.
15. Kaur G, Gonsalves L, Thacker HL. Premenstrual dysphoric disorder: a review for the treating practitioner. Cleveland Clinic Journal of Medicine 2004;71:303–22.
16. National Prescribing Centre. Tackling premenstrual syndrome.  MeReC Bulletin Liverpool: NHS, 2003; 13: 9-12. (accessed  30 March 2009).
17. Guidelines and Audit Committee. Management of premenstrual syndrome.  Green-top guideline No. 48. London: Royal College of Obstetricians and Gynaecologists, 2007. (accessed 30 March 2009).
18. National Prescribing Service. Sertraline (Zoloft), fluoxetine (Lovan, Prozac) for premenstrual dysphoric disorder (PMDD) NPS RADAR December 2004. Sydney: National Prescribing Service, 2004. (accessed 30 March 2009).
19. Kornstein SG, Smith KC. Antidepressant treatment of premenstrual syndrome and premenstrual dysphoric disorder. Primary Psychiatry 2004;11:53–7.