2. Long term RX with AD’s 6 months after the initial 12 week RX? Some may need longer treatment Withdraw slowly! (paroxetine and venlafaxine)

3. Antidepressants-Caveats Efficacy limitations-lack of response in many patients Need for close monitoring (weekly monitoring) for agitation/anxiety and suicidal ideation/behaviour in the first 6-8 weeks 2-4 weeks delay in onset of symptom relief Lack of full remission Risk of relapse Discontinuation syndrome (Paroxetine and Venlafaxine) Sexual dysfunction

4. Other RX choices Lack of response Tolerability issues

5. Pregabalin-Calcium channel Modulator Anti-anxiety effects Analgesic effects Antiepileptic effects

6. Pregabalin (Alpha 2 gamma ligands) Structurally, PGB is an alkylated analogue of GABA Unlike GABA it has no direct or indirect GABAergic activity In contrast to BDZs which bind to a modulatory site on the GABA receptor complex to augment the inhibitory effects of GABA, available data suggest that PGB’s mechanism of action is presynaptic inhibition of excitatory neurotransmission (glutamate..). PGB binds to Alpha2 Gamma subunit of voltage gated calcium channels (VGCC). Resulting in reduction in the release of excitatory neurotransmitters

7. Pregabalin GAD phase II and III programme 1. Montgomery SA. Expert Opin Pharmacother. 2006; 7: 2139–2154. 2. Pohl RB, et al. J Clin Psychopharmacol. 2005; 25: 151–158. 3. Kasper S, et al. A placebo controlled study of pregabalin and venlafaxine in the treatment of Generalised Anxiety Disorder. Poster presented at the 14th Collegium Internationale Neuro-Psychopharmacologicum (CINP) Congress; Paris, France; 20–24 June 2004. 4. Montgomery SA, et al. J Clin Psychiatry. 2006: 67: 771–782. 5. Pande AC, et al. Am J Psychiatry. 2003; 160: 533–540. 6. Feltner DE, et al. J Clin Psychopharmacol. 2003; 23: 240–249. 7. Pande A,C et al. Int J Neuopsychopharmacol. 2000 3 (suppl 1) S344. Abstract P.P30.025. 8. Rickels K, et al. Arch Gen Psychiatry. 2005; 62: 1022–1030. 9. Montgomery S, et al. Brit J Psychiatry. 2008; 193: 389–394. 10. Feltner D, et al. Int Clin Psychopharmacol. 2008; 23: 18–28. 1 fixed-dose versus placebo (TID/BID) 6 weeks 2 5 fixed-dose versus placebo 4–6 weeks 3–7 1 fixed-dose versus placebo, 6-month relapse 10 1 flexible-dose versus placebo elderly, 8 weeks 9 1 positive control venlafaxine-IR 3,4 Positive control alprazolam 8 3 positive controls lorazepam IR 5–7 8 randomised, double-blind, placebo-controlled studies total n=2942 1 BID, Twice daily; TID, Three times daily.

8. Pregabalin-steady state Achieved within 24-48 hours Therefore therapeutic effects are seen quite quickly Relief of symptoms of GAD as reflected by HAMA was observed by 1 week Mean half life is 6.3 hours

9. Pregabalin-Dosing and withdrawal Starting dose - 75mg BD Slowly titrate against symptoms and SE’s upwards to 300mg daily Max dose 600 mg daily and many do not need this Lower doses in elderly if they have renal impairment Withdraw slowly over at least a week. Abrupt withdrawal not recommended

10. Pregabalin has a unique mechanism of action for the effective treatment of GAD Significant reduction in HAM-A scores from week 1 1,2 Significant improvement in both psychological and somatic symptoms at 300–600mg/day 2 Anxiolytic efficacy is similar to a benzodiazepine 3 Significant reduction in risk of relapse over 6 months compared with placebo 4 Well tolerated, with a favourable safety profile 2,5,6 Unique anxiolytic mechanism of action offering a different treatment option for GAD 2,3 1. Data on file – PGB025 “PEACE Data” Pfizer Ltd. 2. Montgomery SA. Expert Opin Pharmacother 2006: 7; 2139–2154. 3. Rickels K, et al. Arch Gen Psychiatry 2005: 62; 1022–1030. 4. Feltner D, et al. Int Clin Psychopharmacol. 2008; 23: 18–28. 5. Data on file – PGB023 (AE summary GAD) Pfizer Ltd. 6. LYRICA ® Summary of Product Characteristics 2008.

11. Most common adverse events and discontinuation rates with pregabalin versus placebo Pregabalin all doses* (n=1149)Placebo (n=484) Adverse events (%) Discontinuations (%) Adverse events (%) Discontinuations (%) Dizziness 31.12.58.90.6 Somnolence 29.24.011.61.2 Dry mouth 15.10.36.40.0 Infection 10.20.08.10.2 Nausea 9.81.09.30.6 Amblyopia 7.50.92.10.0 Incoordination 7.11.0 0.0 Constipation 6.20.23.10.2 Thinking abnormal 6.11.12.30.2 ns, not significant versus placebo at any dose or overall. Adverse events occurring in >5% of pregabalin-treated patients and greater than with placebo-controlled GAD studies. *Pregabalin 150mg/day (TID), 200mg/day (BID), 300mg/day (TID), 400mg/day (BID), 450mg/day (TID), 600mg/day (BID) or 600mg/day (TID). Data on file – PGB023 (AE summary GAD) Pfizer Ltd.