Escitalopram (Lexapro, Esipram) for generalised anxiety disorder and social anxiety disorder (social phobia) Escitalopram (Lexapro, Esipram) for generalised anxiety disorder and social anxiety disorder (social phobia)

PBS listing | Reason for PBS listing | Place in therapy | Safety issues | Dosing issues | Information for patients and carers | References

(ES-sigh-TAL-o-pram)

PBS listing

Restricted benefit

Escitalopram is listed on the Pharmaceutical Benefits Scheme (PBS) as a restricted benefit for the treatment of major depressive disorder. The PBS listing has been extended to the treatment of moderate to severe generalised anxiety disorder (GAD) and moderate to severe social anxiety disorder (SAD, or social phobia [see Box 1]), in people for whom:

• non-pharmacological therapies have failed; and
• for whom a General Practice Mental Health Care Plan has been prepared; or
• assessment by a psychiatrist has occurred.¹

PBS-subsidised continuing treatment is available for people prescribed escitalopram before 1 March 2008 who may not have a GP Mental Health Care Plan, or have not been seen by a psychiatrist.

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee (PBAC) accepted trial data on the effectiveness of escitalopram compared with placebo for reducing anxiety in moderate to severe GAD and moderate to severe SAD. There are currently no other PBS-subsidised treatments for GAD or SAD, so listing was recommended on the basis of acceptable cost-effectiveness compared with placebo.²

To avoid use in populations in which there is no proven benefit (for example, people with mild anxiety), the PBAC restricted the listing of escitalopram to patients whose anxiety symptoms do not respond to non-pharmacological therapy. Non-pharmacological therapy in this context includes both formal psychological therapy and informal psychological therapy (for example, supportive counselling) provided by a GP. Patients can access a range of psychological services under the Medicare Benefits Scheme.

This listing requires that a GP prepare a Mental Health Care Plan to promote appropriate assessment and a structured approach to care, or that a psychiatrist assesses the patient.

Place in therapy

Escitalopram is a selective serotonin reuptake inhibitor (SSRI) and the active isomer of citalopram. SSRIs are a recommended initial pharmacological option for long-term treatment of anxiety disorders.^3,4 Other antidepressants are indicated for GAD and SAD but are not PBS subsidised for these indications. Paroxetine and venlafaxine are TGA approved for both disorders, and sertraline for SAD.⁵

Evidence for the efficacy of escitalopram is limited to patients with a primary diagnosis of moderate to severe GAD or moderate to severe generalised SAD, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders — 4th edition (DSM-IV) (see Box 1). It does not relate to mildly anxious patients, for whom other forms of treatment are more appropriate.

Box 1: Generalised anxiety disorder (GAD) and social anxiety disorder (SAD, or social phobia)

Escitalopram was shown in trials to be more effective than placebo in reducing anxiety in more severe forms of GAD and SAD. There is no evidence that it is more effective than other SSRIs in these indications.

Psychological therapies, including cognitive behavioural therapy (CBT), are also an effective initial option for anxiety disorders.^3,4,7–9 Consider escitalopram in conjunction with a structured plan of care for people with moderate to severe GAD or SAD who fail to respond to non-pharmacological therapies alone.

Aim to control symptoms and improve social functioning

The main treatment options for anxiety disorders include psychological therapy, pharmacological therapy and self-help strategies.^3,4,7,8 Choose a treatment based on factors including:

• patient preference
• type, severity and persistence of anxiety
• presence of psychiatric or physical comorbidity
• response to previous treatments
• availability of psychological therapies.⁴

Try non-pharmacological therapies first

Psychological therapies are effective and should be offered as an initial treatment option to people with GAD and SAD.^7,8 Cognitive behavioural therapy is likely to be at least as effective as pharmacological therapy in the treatment of GAD and SAD, and possibly with longer-term benefits.^10–13 When available and acceptable to the patient, offer an adequate course of CBT (for example weekly sessions of 1–2 hours for up to 4 months).³ Internet-based psychological interventions may be useful for some patients³ (see Resources for patients and clinicians). While combining CBT with pharmacological therapy may help patients who are not responding to an adequate trial of either treatment alone, there is little trial evidence to inform this approach.¹¹

Efficacy of escitalopram in practice may be lower than expected from trial results

The clinical relevance of small but statistically significant treatment differences between escitalopram and placebo, as seen in clinical trials, remains unclear. Patients with significant physical or psychiatric comorbidity, substance dependence or recent psychotropic drug use were excluded from the trials, thus limiting the generalisability of the results to the general population, in which comorbidity is common.¹⁴

Anxiety and depression often coexist.^15–17 Although patients with major depressive disorders were excluded from these escitalopram trials, it is likely that some patients had some level of underlying depression. Improvement in anxiety scores and response rates could have been partially due to improvement in depressive symptoms.

Review response to treatment with escitalopram

In patients who improve with drug treatment, guidelines recommend continuing for at least 6 months and reviewing the patient at 8–12-week intervals.³

If there is no improvement by 12 weeks using an optimal dose of escitalopram, consider another SSRI, or other form of therapy.^3,4 Consider referral to a specialist mental health service or psychiatrist for patients with significant symptoms despite an adequate trial of two pharmacological interventions.³

There are data showing that treatment effects were maintained while patients continued to take escitalopram (for up to 76 weeks in GAD and up to 24 weeks in SAD), but no long-term follow-up on outcomes after drug treatment is withdrawn.

More effective than placebo in GAD but treatment differences were small

In short-term trials of 8–12 weeks involving patients with moderate to severe DSM-IV-defined GAD, escitalopram provided greater improvements than placebo in anxiety scores (primary outcome) and in response and remission rates.^18,19 However, treatment differences between the groups were small, and both escitalopram- and placebo-treated patients achieved substantial improvements from baseline. Response rates were high with placebo and only about 19% lower than with escitalopram (28.6% versus 47.5% with escitalopram) in a pooled analysis.²⁰ Another potential limitation is that the Hamilton Anxiety Scale (HAMA)* may not have differentiated well between symptoms of anxiety and depression.⁸

*The Hamilton Anxiety Scale (HAMA) is a 14-item clinician-rated scale scored on a 5-point categorical scale used to quantify the severity of GAD: 18+ mild, 25+ moderate, 30+ severe anxiety.²¹

Modest efficacy in generalised SAD

In short-term trials of 12–24 weeks involving patients with severe DSM-IV-defined generalised SAD, escitalopram was more effective than placebo in reducing anxiety as measured by the Liebowitz Social Anxiety Scale (LSAS)^† total score.^22,23 The differences between escitalopram and placebo in reducing anxiety scores after 12 weeks of treatment were small and of uncertain clinical significance (for example, 7.3 points in one trial on a scale of 0 to > 100).²² Despite higher overall response rates with escitalopram compared with placebo, most patients remained symptomatic and persisted to have 'moderate' SAD with either treatment.^22,23

^†The Liebowitz Social Anxiety Scale (LSAS) is a 24-item clinician-rated scale scored on a 4-point categorical scale. The LSAS measures severity of fear and avoidance in performance and social situations (13 items describe performance situations and 11 describe social situations): 55–65 moderate, 65–80 marked, 80–95 severe, > 95 very severe social phobia.²⁴

Efficacy maintained for initial responders with continued treatment

Data from an open-label trial showed that people with GAD who initially responded to escitalopram continued to improve with a further 6 months of unblinded treatment.²⁵ In a relapse-prevention trial, participants who continued with escitalopram had lower relapse rates (19%) compared with those who switched to placebo (56%) (hazard ratio [HR] 4.04, 95% confidence interval [CI] 2.75 to 5.94) over 24–76 weeks.²⁶

In a similar relapse-prevention trial in SAD, 22% of the escitalopram group compared with 50% of the placebo group relapsed by 24 weeks (p < 0.001).²⁷ Over the 24-week double-blind phase further improvement occurred in the escitalopram group (–8.3 points on the LSAS) compared with a deterioration in the placebo group (+4.5 points on the LSAS).²⁷ Note that only half the patients who switched from escitalopram to placebo had relapsed by the end of the study.

No better than paroxetine

There are limited data comparing escitalopram with other SSRIs. Secondary efficacy analyses of two studies (one in GAD and one in SAD) found that escitalopram 10–20 mg daily was more effective than paroxetine 20 mg daily ^19,23, but the studies were not powered for this effect. The fixed daily dose of paroxetine in these studies may account for the observed superiority of escitalopram. One study in GAD found escitalopram (10–20 mg daily) and flexible-dose paroxetine (20–50 mg daily) to have similar efficacy.²⁸ More patients receiving paroxetine withdrew during the 24-week double-blind period (47% versus 36% for escitalopram) and there were more withdrawals in the paroxetine group because of adverse events (23% versus 6.6% for escitalopram). The overall incidence of treatment-related adverse events was similar for paroxetine (89%) and escitalopram (77%).²⁸

Large placebo response suggests that not all the therapeutic response seen was due to escitalopram

Placebo response rates were high^18,19,22,23, particularly in the first few weeks of treatment. This suggests that the severity of GAD and SAD may vary over time or with non-drug therapy (e.g. regular inquiry about an individual). Some trials employed a 1-week, single-blind, placebo lead-in period, after which only those who continued to meet the original inclusion criteria were included in the double-blind trial.^18,19,22,23 This may have contributed to a larger treatment effect observed for escitalopram at the end of the study period after the placebo response started to plateau.

Safety issues

Common adverse effects, particularly in the first few weeks of treatment, include insomnia, nausea and sexual problems.²⁹

The most frequent adverse effects reported with escitalopram in clinical trials included nausea (18% versus 8.4% with placebo), insomnia (9.3% versus 4.6%), fatigue (8.7% versus 3.5%), somnolence (8.2% versus 3.5%), increased sweating (5.5% versus 1.5%), ejaculation disorders (4.7% versus 0.5%) and anorgasmia (2.9% versus 0.3%).²⁹ The incidence rates of common adverse effects in patients treated with escitalopram 20 mg daily was about double that seen with escitalopram 10 mg daily.²⁹

In a pooled analysis of three placebo-controlled trials, discontinuation due to adverse effects was twice as high in the escitalopram group compared with the placebo group (8% versus 4%).²⁰

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Monitor carefully in the first few weeks of treatment

Warn patients about the possibility of a transient worsening of anxiety, agitation, insomnia and other symptoms at the start of treatment and during dose titration. Guidelines recommend careful and regular monitoring in the first few months of SSRI treatment (within 2 weeks of starting therapy, fortnightly for 6 weeks and then at 12 weeks).³

Monitor patients with comorbid depression for clinical worsening and suicidality

Regulators recommend close monitoring and frequent follow-up of all patients during the early stages of treatment with an antidepressant and during dosage adjustment.^30–32 Assess patients with comorbid depression for worsening clinical symptoms, suicidality or unusual behaviour. Patients with a history of suicide-related thoughts or behaviours before starting treatment may be at highest risk.²⁹

Avoid escitalopram in children and adolescents

The safety and efficacy of escitalopram have not been established in children and adolescents (under the age of 18 years) and it is not approved for use in these groups.²⁹ There are data to show that use of antidepressants (for several indications) may increase the risk of suicidal thoughts and behaviours in children and adolescents (0–18 years: odds ratio [OR] 2.22, 95% CI 1.40 to 3.60) and suicidal behaviour among young adults (18–24 years: OR 2.31, 95% CI 1.02 to 5.64) compared with placebo.³¹ This information has prompted changes to the product information in Australia and in other countries.^30–32

Specialist input is advisable when treating children with anxiety disorders.⁵

Reduce the dose slowly to avoid discontinuation or withdrawal symptoms

When stopping escitalopram, gradually taper the dose over at least 1–2 weeks to avoid discontinuation or withdrawal symptoms (for example, dizziness, sensory disturbances including paraesthesia, anxiety and agitation, sleep disturbances, tremor, sweating, confusion).^5,29 Slower dose titration may be needed for patients who experience these symptoms.

Dosing issues

The recommended dose of escitalopram in GAD and SAD is 10 mg daily, increasing to a maximum of 20 mg daily if required. Escitalopram should be taken as a single dose in the morning or evening with or without food.³³

Minimise adverse effects by starting at a low dose (consider halving the normal starting dose) and increasing gradually after 2–4 weeks until the optimal dose is achieved.⁵

Reduce doses for people with hepatic impairment (start with 5 mg daily then increase to a maximum of 10 mg daily if required).²⁹ Do not exceed 10 mg daily in people older than 65 years. Use with caution in people with severe renal impairment (creatinine clearance < 20 mL/min) as there is a lack of data in this group.²⁹

Escitalopram is available as a tablet and oral liquid formulation, although the oral liquid is not currently listed for GAD and SAD.

Avoid co-prescribing escitalopram with other drugs that can increase serotonin levels

Escitalopram may interact with other serotonergic drugs to cause serotonin toxicity (also known as serotonin syndrome). These drugs include other SSRIs, venlafaxine, tricyclic antidepressants, monoamine oxidase inhibitor antidepressants (including moclobemide), triptans, tramadol, pethidine, fentanyl, St John's wort and the illicit drugs MDMA ('ecstasy'), cocaine and LSD.^5,29,34

Serotonin toxicity can range from mild to life threatening.³⁴

Information for patients and carers

Advise patients and carers of the following.

• The benefits of escitalopram in reducing anxiety may not be immediate and can take a few weeks to appear.
• GAD and SAD are chronic conditions and treatment for at least 6 months may be required.
• Psychological therapies including cognitive behavioural therapy are effective in GAD and SAD. Psychological treatments subsidised by Medicare are available for GAD and SAD.
• Common side effects of escitalopram include nausea, insomnia, fatigue, somnolence, increased sweating, ejaculation disorders and anorgasmia.
• Tell your doctor immediately if you experience suicidal or self-harm–related thoughts or behaviours.
• Stopping escitalopram abruptly may cause withdrawal symptoms, including dizziness, paraesthesia (pins and needles or numbness of the skin), anxiety and agitation, sleep disturbances and other symptoms.
• Check with your doctor or pharmacist before using any prescription medicines or over-the-counter medicines (including herbal preparations) while taking escitalopram, as interactions may occur.

Provide information about face-to-face and online support services available for people with anxiety disorders (see Resources for patients and clinicians).

Discuss the [Lexapro; Esipram] consumer medicine information (CMI) leaflet.

Resources for patients and clinicians

• Black Dog Institute (with links to organisations that run or co-ordinate mental health support groups around Australia)
• Beyondblue (the national depression initiative, with links to information about anxiety and anxiety disorders)
• CRUFAD (Clinical Research Unit for Anxiety and Depression) (information for patients and clinicians about anxiety and other mental health disorders)
• Climate TV (interactive information about anxiety for patients and clinicians)
• MoodGYM (interactive training program in cognitive behavioural therapy for patients)
• The University of Queensland Online Anxiety Prevention Project (interactive training program in self help/cognitive behavioural therapy for patients)

References

1. Australian Government Department of Health and Ageing. Positive recommendations made by the PBAC — March 2008. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-mar08-positive (accessed 25 June 2008).
2. Australian Government Department of Health and Ageing and Lundbeck Australia Pty Ltd. Short minutes of March 2008 PBAC meeting. (Draft) Data on file.
3. National Institute for Health and Clinical Excellence (NICE). Anxiety (amended). Management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. 2007. http://www.nice.org.uk/guidance/index.jsp?action=download&o=29641 (accessed 25 June 2008).
4. Baldwin DS, Anderson IM, Nutt DJ, et al. British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2005;19:567–96. [PubMed]
5. Rossi S, ed. Australian Medicines Handbook. Adelaide, 2008.
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edn. Washington, DC, 1994.
7. Therapeutic Guidelines Ltd. Therapeutic guidelines: Psychotropic. 2003. Version 5.
8. Swinson R, Antony M, Bleau P, et al. Clinical practice guidelines: Management of Anxiety Disorders. Can J Psychiatry 2006;51:1S–92S. http://ww1.cpa-apc.org:8080/Publications/CJP/supplements/july2006/anxiety_guidelines_2006.pdf
9. New Zealand Guidelines Group (NZGG) National Health Committee. Guidelines for Assessing and Treating Anxiety Disorders. 1998. http://www.nzgg.org.nz/guidelines/0038/Anxiety_guideline.pdf (accessed 25 June 2008).
10. McIntosh A, Cohen A, Turnbull N, et al. Clinical guidelines and evidence review for panic disorder and generalised anxiety disorder. Sheffield: University of Sheffield/London: National Collaborating Centre for Primary Care, 2004. http://www.nice.org.uk/guidance/index.jsp?action=download&o=29636 (accessed 25 June 2008).
11. Davidson J, Foa E, Huppert J, et al. Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia. Arch Gen Psychiatry 2004;61:1005–13. [PubMed]
12. Clark D, Ehlers A, McManus F, et al. Cognitive therapy versus fluoxetine in generalized social phobia: a randomized placebo-controlled trial. J Consult Clin Psychol 2003;71:1058–67. [PubMed]
13. Haug T, Blomhoff S, Hellstrøm K, et al. Exposure therapy and sertraline in social phobia: 1-year follow-up of a randomised controlled trial. Br J Psychiatry 2003;182:312–8. [PubMed]
14. Australian Institute of Health and Welfare (AIHW) 2006. Australia's Health 2006. http://www.aihw.gov.au/publications/aus/ah06/ah06-c00.pdf (accessed 25 June 2008).
15. McLennan W. Mental health and wellbeing: Profile of adults, Australia. Canberra: Australian Bureau of Statistics, 1997. http://www.ausstats.abs.gov.au/Ausstats/subscriber.nsf/0/CA25687100069892CA25688900233CAF/$File/43260_1997.pdf (accessed 25 June 2008).
16. Australian Bureau of Statistics. National Health Survey: Mental Health, Australia, 2001. Canberra: ABS, 2001. http://www.ausstats.abs.gov.au/ausstats/subscriber.nsf/0/E7621A9758D3A4B5CA256DF1007C0637/$File/48110_2001.pdf (accessed 25 June 2008).
17. Australian Bureau of Statistics. Mental Health in Australia: A Snapshot, 2004–05. Canberra: ABS, 2006. http://www.abs.gov.au/AUSSTATS/abs@.nsf/Lookup/4824.0.55.001Main+Features12004-05?OpenDocument# (accessed 25 June 2008).
18. Davidson J, Bose A, Korotzer A, et al. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study. Depress Anxiety 2004;19:234–40. [PubMed]
19. Baldwin D, Huusom A, Maehlum E. Escitalopram and paroxetine in the treatment of generalised anxiety disorder: randomised, placebo-controlled, double-blind study. Br J Psychiatry 2006;189:264–72. [PubMed]
20. Goodman W, Bose A, Wang Q. Treatment of generalized anxiety disorder with escitalopram: pooled results from double-blind, placebo-controlled trials. J Affect Disord 2005;87:161–7. [PubMed]
21. The Anxiety Community. Hamilton Anxiety Scale (HAMA). http://www.anxietyhelp.org/information/hama.html (accessed 25 June 2008).
22. Kasper S, Stein D, Loft H, et al. Escitalopram in the treatment of social anxiety disorder: randomised, placebo-controlled, flexible-dosage study. Br J Psychiatry 2005;186:222–6. [PubMed]
23. Lader M, Stender K, Bürger V, et al. Efficacy and tolerability of escitalopram in 12- and 24-week treatment of social anxiety disorder: randomised, double-blind, placebo-controlled, fixed-dose study. Depress Anxiety 2004;19:241–8. [PubMed]
24. The Anxiety Community. Liebowitz Social Anxiety Scale (LSAS). http://www.anxietyhelp.org/information/leibowitz.html (accessed 25 June 2008).
25. Davidson J, Bose A, Wang Q. Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder. J Clin Psychiatry 2005;66:1441–6. [PubMed]
26. Allgulander C, Florea I, Huusom A. Prevention of relapse in generalized anxiety disorder by escitalopram treatment. Int J Neuropsychopharmacol 2006;9:495–505. [PubMed]
27. Montgomery S, Nil R, Dürr-Pal N, et al. A 24-week randomized, double-blind, placebo-controlled study of escitalopram for the prevention of generalized social anxiety disorder. J Clin Psychiatry 20056;6:1270–8. [PubMed]
28. Bielski R, Bose A, Chang C. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Ann Clin Psychiatry 2005;17:65–9. [PubMed]
29. Lundbeck Australia Pty Ltd. Lexapro product information. July 2007.
30. Australian Government Department of Health and Ageing, Therapeutic Goods Administration (TGA). Suicidality with SSRIs: adults and children. Aust Adv Drug Reactions Bull 2005; 24. http://www.tga.gov.au/adr/aadrb/aadr0508.htm (accessed 25 June 2008).
31. Co-ordination Group for Mutual Recognition and Decentralised Procedures — Human ChPWP. Antidepressants and suicidal thoughts and behaviour. 2008. http://www.hma.eu/uploads/media/PAR_suicidal_thoughts_in_antidepressants.pdf (accessed 25 June 2008).
32. U.S. Food and Drug Administration (FDA). Revisions to Product Labeling: Suicidality and Antidepressant Drugs. 2007. http://www.fda.gov/cder/drug/antidepressants/default.htm (accessed 25 June 2008).
33. Lundbeck Australia Pty Ltd. Lexapro consumer medicine information. May 2007.
34. Isbister G, Buckley N, Whyte I. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 2007;187:361–5. [PubMed]