David S. Baldwin Reader in Psychiatry 1 and Honorary Consultant Psychiatrist 2

1. Antidepressant drugs in the treatment of Generalised Anxiety Disorder – what is known and what remains uncertain? David S. Baldwin Reader in Psychiatry 1 and Honorary Consultant Psychiatrist 2 1. Clinical Neuroscience Division, School of Medicine, University of Southampton 2. Mood and Anxiety Disorders Service, Hampshire Partnership Trust

3. Declaration of interests • I do not have shares in any pharmaceutical company, nor do family members • I do not accept any personal retainer from any pharmaceutical company • I have acted as a consultant to a number of companies with an interest in anxiety disorders (Asahi, AstraZeneca, Cephalon, Eli Lilly, GSK, Lundbeck, Organon, Pharmacia, Pierre Fabre, Pfizer, Roche, Servier, Sumitomo, Wyeth) • I hold or have held research grants (on behalf of my employer) from a number of companies with an interest in anxiety and depressive disorders (Cephalon, Eli Lilly, GSK, Lundbeck, Organon, Pfizer, Pharmacia, Roche, Wyeth) • I have accepted paid speaking engagements in industry supported satellite symposia at international and national meetings • I do not accept hospitality or travel not related to a speaking engagement • I am co-author of the British Association for Psychopharmacology evidence-based guidelines on the treatment of anxiety disorders • I am a medical patron of the National Phobics Society

4. Outline of talk • recent evidence-based guidelines for GAD • response rates to initial treatment approaches • predictors of response to treatment • duration of treatment after response • management approaches after initial non-response • future treatments and guidelines

5. 1. Recent guidelines for treatment of GAD

6. www.bap.org.uk

7. Summary of BAP guidelines for GAD • choose an evidence-based treatment • take account of clinical features, patient preference, and availability • consider an SSRI for first-line treatment • treatment periods of up to 12 weeks may be needed to fully assess efficacy • routine combination with psychological treatments is not recommended • continue treatment for at least 6 months in patients who have responded • use a treatment known to be efficacious in preventing relapse • monitor efficacy and tolerability during long-term treatment • after non-response to initial treatment, consider: • switch to other evidence-based treatment • combining drug treatment with cognitive-behaviour therapy • combining treatment only when there are no contraindications • referral to specialist services in refractory patients Baldwin DS et al. J Psychopharmacol 2005: 19: 567-596

8. Canadian guidelines for drug treatment in GAD Canadian Psychiatric Association. Can J Psychiatr 2006; 51: 9S-91S.

9. 2. Response rates to initial treatment

10. Response rates with SSRIs in acute treatment double-blind randomised placebo-controlled studies * p < 0.05; ** p < 0.01; *** p < 0.001, advantage for active treatment over placebo

11. Response rates with SNRIs in acute treatmentdouble-blind randomised placebo-controlled studies p < 0.05; ** p < 0.01; *** p < 0.001, advantage for active treatment over placebo #, mean CGI-I score, ## estimates from published figure; NR not reported, NS not significantly different from placebo

12. Fixed-dose escitalopram and paroxetine in GADreduction in mean HAMA score p < 0.05, ** p < 0.01, *** p < 0.001, versus placebo; # p < 0.05 versus paroxetine mean HAMA scores at baseline placebo 27.1, ESC 5 27.1, ESC 10 26.0, ESC 20 27.7, PAR 27.3 Baldwin et al. Br J Psychiatry 2006; 189: 262-272

13. Pregabalin in acute treatment of GADEndpoint (LOCF) CGI-I responder rates 70 * ** ** * ** * 60 ** ** 50 * 40 CGI-I responder rates (%) 30 20 10 0 PBOn=85 PGB 300 n=89 PGB450n=88 PGB600n=85 ALP 1.5 n=88 PBOn=83 PGB200n=75 PGB400n=85 PGB450n=85 PBOn=100 PGB400n=94 PGB600n=104 VEN75n=110 Total daily dose Rickels et al 2005 (4 wks) Montgomery et al 2006 (6 wks) Pohl et al 2005 (6 wks) †Responder rate defined as CGI-I of 1 or 2; *p<0.05 vs placebo; **p<0.01 vs placebo

14. Efficacy vs. effectiveness of benzodiazepinessystematic review and meta-analysis of RCTs Withdrawals due to lack of efficacy Withdrawals for any reason Martin JLR et al. J Psychopharmacol 2007; 21: 774-782

15. RCTs of antidepressant treatment in elderly GAD * p < 0.05; ** p < 0.01, vs placebo; # 30/34 patients had GAD; § HAMA-response, not significant

16. Pregabalin in acute treatment of older patientsresponse (reduction in HAMA by 50% or more) rates Montgomery SA et al. Br J Psychiatry. In press

17. What equates to symptom remission in GAD? Bandelow et al. J Clin Psychiatry 2006; 67: 1428-1434

18. Fixed-dose escitalopram and paroxetine in GADsymptomatic remission (HAMA score < 7) * p < 0.05, ** p < 0.01, *** p < 0.001, versus placebo; # p < 0.05 versus paroxetine Baldwin et al. Br J Psychiatry 2006; 189: 262-272

19. Symptomatic remission with paroxetine in GAD * * ** * ** # * p < 0.05, ** p < 0.01 vs placebo; # 20-mg and 40-mg groups combined Rickels et al. J Clin Psychiatry 2006; 67: 41-47

20. 3. Prediction of response to treatment

21. Predictors of good and poor response in GAD • shorter duration of symptoms (venlafaxine, fluoxetine)1, 2 • co-morbid dysthymia (venlafaxine)1, psychiatric co-morbidity3 • history of depression, panic disorder (venlafaxine)4 • severity of psychosocial impairment (TAU) 3 • lower symptom severity (escitalopram) 5 • history of benzodiazepine use (venlafaxine) 4 • longer duration of untreated illness (SSRI, venlafaxine) 6 1. Perugi G et al. Neuropsychobiol 2002; 46: 145-149 2. Simon NM et al. Depress Anx 2006; 23: 373-376 3. Rodriguez BF et al. J Nerv Ment Dis 2006; 194: 91-97 4. Pollack M et al. J Clin Psychopharmacol 2003; 23: 250-259 5. Stein DJ et al. J Clin Psychiatry 2006; 67: 1741-1746 6. Altamura CA et al. CNS Spectrums 2008; 13: 415-422

22. Early onset of effect and subsequent response 1. Downing and Rickels. Acta Psychiatr Scand 1985; 72: 522-528 2. Laakmann et al.Psychopharmacol 1998; 136: 357-366 3. Rynn et al. Depress Anx 2006; 23: 461-465 4. Pollack et al. J Psych Res 2008. In press 5. Baldwin et al. Unpublished findings

23. Onset of action and remission with duloxetineproportion achieving remission (HAMA <7) at endpoint Degree of reduction in HAMA score at week 2 and week 4 Pollack MH et al. J Psych Res 2008. In press.

24. Early onset of effect and later overall responseanalysis of the escitalopram clinical trial database Baldwin DS et al, submitted for publication. Poster presentation at 2nd IADC, Cape Town, March 2008

25. 4. Duration of treatment after response

26. Clinical outcomes in anxiety disordersprospective, naturalistic, longitudinal (12 year) study (HARP) recovery: at least 8 consecutive weeks with at most residual symptoms recurrence: full diagnostic criteria for minimum period (2 weeks, other than GAD) Bruce et al. Am J Psychiatry 2005; 162: 1179-1187

27. Outcome of DSM-III defined GAD in the Zurich Studyprospective epidemiological study, 22-year follow-up (n=105) ‘These results are clearly at odds with the common affirmation that GAD has a generally chronic course, but are compatible with the description of a waxing and waning course: however our data show that waning is more common than waxing’. Angst J, Gamma A, Baldwin DS et al. Eur Arch Psychiatry Clin Neurosci. In press.

28. Placebo-controlled relapse prevention studies *** p < 0.001 vs placebo *** *** *** *** n=168 n=278 n=288 n=187 n=188 n=170 pregabalin, 24 wks paroxetine, 24 wks escitalopram, 24-72 wks duloxetine, 24 wks Feltner et al. Int Clin Psychopharmacol 2008; 23: 18-28; Stocchi et al. J Clin Psychiatry 2003; 64: 250-258; Allgulander et al. Int J Neuropsychopharmacol 2006; 9: 495–505; Korb et al. Presented at IADS Cape Town, March 2008

29. 5. Management after initial non-response

30. Possible treatment options after non-response • increase in dose • switch to alternative pharmacological treatment • SNRI • pregabalin • buspirone • agomelatine • quetiapine • augmentation with olanzapine or risperidone • combination drug and psychological treatment • use of complementary approaches

31. SSRIs versus psychic and somatic symptomsdouble-blind placebo-controlled fixed-dose studies Boxes show significant differences from placebo ( < 0.05, or less)

32. SNRIs versus psychic and somatic symptomsdouble-blind placebo-controlled fixed-dose studies Boxes show significant differences from placebo (p< 0.05, or less)

33. Azapirones in acute treatment of GAD • efficacious in acute treatment especially if benzodiazepine-naïve • less well tolerated than benzodiazepines Chessick CA et al. Cochrane Database Syst Rev 2006; 3: CD006115

34. Agomelatine in acute treatment of GADrandomised double-blind flexible-dose placebo-controlled 12-week study * p = 0.026 * p = 0.027 Mean baseline HAMA scores: placebo 28.6, agomelatine 29.0 Stein DJ et al. Eur Neuropsychopharmacol 2007; 17 (suppl. 4): S509-510

35. Antipsychotic augmentation after non-responsechange in HAMA score and response on CGI-I * NS * * p < 0.05 Pollack MH et al. Biol Psychiatry 2006; 59: 211–215 (mean olanzapine daily dose 8.7 + 7.1 mg, following fluoxetine 20mg/day) Brawman-Mintzer et al. J Clin Psychiatry 2005; 66: 1321–1325 (mean risperidone daily dose 1.1 mg, following range of drugs)

36. Quetiapine in acute treatment of GADrandomised double-blind fixed-dose placebo-controlled 8-wk study (LOCF, modified ITT) Mean baseline HAMA scores: placebo 27.3, QUET 50 mg 26.9, QUET 150 mg 26.6, PAR 20 mg 27.1 Bandelow B et al. Int J Psychiatry Clin Pract 2007; 11: 314-315 (abstract)

37. Complementary medicine in GAD Connor KM, Davidson JRT. Int Clin Psychopharmacol 2006; 21: 249-253. Woelk H et al. J Psychiatr Res 2007; 41: 472-480. Herrera-Arettano et al. Planta Med 2007; 73: 713-717.

38. Combining CBT and drug treatment in GAD • due to lack of data, not currently possible to draw conclusions for GAD • continuing need for large RCT of CBT vs SSRI vs [CBT+SSRI] Bandelow B et al. World J Biol Psychiatr 2007; 8: 175-187

39. 6. Future developments in drug treatment

40. Emotion recognition and anxiety disorders recent cross-sectional studies indicate attentional bias in social phobia high social anxiety associated with selective attention towards threatening images social phobia associated with deficits of discriminating fear from other emotions accuracy of recognition in depression can be enhanced by tryptophan supplementation

41. Correlates of disorder-specific contextual threat processing: Virtual Reality

42. Acute SSRI treatment and cognitive bias in GAD * * * * p < .05 * Mogg, Baldwin et al.Psychopharmacol 2004; 176: 466-470

43. Genetic polymorphisms, efficacy and tolerability • genotyping for cytochrome P450 enzymes might be useful in deciding which SSRI to use and at what dose 1 • selection of drug treatment on the presence of genetic polymorphisms known to be predictive of response or tolerability 2 • 5-HTTLPR polymorphisms predicts response to SSRI in patients with generalised social phobia 3 1. Perlis RH. Br Med J 2007; 334: 259 2. Wong ML, Licinio J. Nature Rev Drug Discovery 2004; 3: 136-151 3. Stein MB et al. Psychopharmacol 2006; 187: 68-72

44. New targets for anxiolytic drugs • [SSRI plus 5-HT1A and 5-HT1B autoreceptor antagonists] • [SSRI plus 5-HT2C antagonists] • melatonin receptor agonists • metabotropic glutamate receptor antagonists • cholecystokinin antagonists • neuropeptide Y agonists • adenosine A1 and A2A receptor agonists • refined enhancement of GABA activity

45. What might be in future BAP guidelines? • recognition of evidence of efficacy in acute treatment agomelatine duloxetine pregabalin quetiapine • reduction in length of initial treatment before assessment • recognition of efficacy of pregabalin in preventing relapse • recommendation for 12 months of treatment after response

46. Expanding the evidence base in GAD • neuropsychobiological measures in response prediction • studies in patients with comorbid depressive disorders • dosage escalation studies after initial non-response • placebo-controlled augmentation studies • pregabalin, buspirone, agomelatine, antipsychotics • large randomised controlled trials of combination treatment versus CBT or drug treatment, when given alone

47. Thank you very much!