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

Duration of treatment after response

Low probability of remission in GAD The Harvard-Brown Anxiety Research Program (a prospective, observational, longitudinal study) was designed to investigate variables that influenced the clinical course of GAD in 167 patients aged 18 years of age Patients were assessed at study enrolment and re-examined at 6–12-month intervals using the Longitudinal Interval Follow-up Evaluation, which generates a 6-point psychiatric status rating (PSR); a PSR score of 6 indicates full DSM-III-R criteria for GAD Full remission was defined as occasional or no symptoms (PSR of 1 or 2) for 8 consecutive weeks Treatment was not controlled over the course of the study, although most patients were taking treatment at some time The probability of full remission over 5 years was low (0.38) Full remission was least likely to occur in patients with poor relationships with their spouse and those with personality disorders Reference Yonkers KA, et al. Br J Psychiatry. 2000; 176: 544–549. *Full remission: Psychiatric Status Rating <3 for 8 weeks following index episode. Adapted from Yonkers KA, et al. Br J Psychiatry. 2000; 176: 544–549. LYG100 January 2009 3

Placebo-controlled relapse prevention studies *** p < 0.001 vs. placebo *** *** *** *** *** n=170 n=168 n=278 n=288 n=187 n=188 n=211 n=213 n=216 n=216 Pregabalin 24 wks Paroxetine 24 wks Escitalopram 24-72 wks Duloxetine 24 wks Quetiapine 52 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; Davidson et al. Eur Neuropsychopharmacol 2008; 18: 673-681; www.astrazeneca.clinicaltrials.com, accessed 10/11/08

Management after initial non-response

Possible treatment options after pharmacological RX non-response increase in dose ? (no clear evidence) switch to alternative treatment pregabalin Buspirone SNRI Benzodiazepines agomelatine Quetiapine CBT augmentation with pregabalin, olanzapine, quetiapine or risperidone or pindolol Combination of 2 evidence based drug treatments when no contraindication (risk of serotonin syndrome in SSRI/SNRI or Mirtazapine combinations) combination drug and psychological treatment? use of complementary approaches

Possible treatment options after psychological RX non-response augmentation with SSRI’s

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

Summary: Treatment of GAD Aims of treatment in GAD are to reduce symptoms of anxiety; to minimise disruption to day-to-day functioning, with minimal adverse effects Effective treatments for GAD include psychological therapy, pharmacological therapy and self-help1 Numerous effective pharmacological therapies exist, including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), Pregabalin, Benzodiazepines, Azapirones…2 Current treatments may have limitations GAD is often inappropriately treated1 Pharmacotherapy is the cornerstone of GAD treatment2 Numerous effective pharmacological therapies exist, including benzodiazepines, tricyclic antidepressants, selective serotonin re-uptake inhibitors, serotonin-noradrenaline re-uptake inhibitors, azapirones and pregabalin1 References Montgomery S, et al. Expert Opin Pharmacother. 2006; 7: 2139–2154. National Institute for Health and Clinical Excellence. CG22 Anxiety: Algorithm (management of Generalised Anxiety Disorder). Available at http://www.nice.org.uk/nicemedia/pdf/CG22AlgorithmGenAnxietyDisorder.pdf. Accessed: March, 2008. National Institute for Health and Clinical Excellence. CG22 Anxiety: Algorithm (management of Generalised Anxiety Disorder). Available at http://www.nice.org.uk/nicemedia/pdf/CG22AlgorithmGenAnxietyDisorder.pdf Accessed: March, 2008. Montgomery SA. Expert Opin Pharmacother. 2006; 7: 2139–2154. LYG100 January 2009 9