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

2. 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

3. Other RX choices
Lack of response
Tolerability issues

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

5. 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

6. Pregabalin GAD phase II and III programme
1 fixed-dose versus placebo (TID/BID)
6 weeks2
5 fixed-dose versus placebo
4–6 weeks3–7
1 fixed-dose versus placebo, 6-month
relapse10
1 flexible-dose versus placebo
elderly, 8 weeks9
1 positive control
venlafaxine-IR3,4
Positive control
alprazolam8
3 positive controls
lorazepam IR5–7
8 randomised, double-blind, placebo-controlled studies
total n=29421
This slide provides an overview of the pregabalin phase II and III clinical development program for pregabalin in GAD
A total of 2942 patients have so far participated in GAD clinical trials1
The programme consists of eight randomised, double-blind, placebo-controlled trials, including six acute treatment studies (4–6 weeks) in adults2–7, one 8-week study in the elderly8, and one 6-month adult relapse prevention study9
These eight studies represent the totality of phase II and III clinical trials of pregabalin in GAD1
Pregabalin doses ranged from 150–600mg/day, twice daily (BID) or three times daily (TID)1
The key inclusion criteria for the phase III studies were a DSM-IV diagnosis of GAD with a minimal HAM-A total score of ≥20, and absence of a current comorbid diagnosis of major depressive disorder, or another DSM-IV anxiety disorder or alcohol or substance abuse/dependence1
Across all adult trials, patients completed a 1-week washout period, followed by rapid dose escalation for 1–6 days to the assigned dose. This was followed by a 1-week taper after the completion of double-blind treatment1
The primary outcome measure in all of the studies except the relapse study was the 14-item HAM-A score; secondary measures included the Clinical Global Impression Improvement scale (CGI-I) and the 17-item Hamilton Depression Rating Scale (HAM-D)1
For the primary outcome measure, the HAM-A at the last-observation carried-forward (LOCF) endpoint1
References
Montgomery SA. Expert Opin Pharmacother. 2006; 7:2139–54.
Pohl RB, et al. J Clin Psychopharmacol. 2005; 25: 151–158.
Kasper S, et al. A placebo controlled study of pregabalin and venlafaxine in the treatment of generalized anxiety disorder. 15th CINP Congress – 20–24 June, Paris, France (2004). Poster.
Montgomery SA, et al. J Clin Psychiatry. 2006; 67: 771–782.
Pande AC, et al. Am J Psychiatry. 2003; 160: 533–540.
Feltner DE, et al. J Clin Psychopharmacol. 2003; 23: 240–249.
Rickels K, et al. Arch Gen Psychiatry. 2005; 62: 1022–1030.
Montgomery S, et al. Brit J Psychiatry. 2008; 193: 389–394.
Feltner D, et al. Int Clin Psychopharmacol. 2008; 23: 18–28.
BID, Twice daily; TID, Three times daily.
1. Montgomery SA. Expert Opin Pharmacother. 2006; 7: 2139– Pohl RB, et al. J Clin Psychopharmacol. 2005; 25: 151– 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 Montgomery SA, et al. J Clin Psychiatry. 2006: 67: 771– Pande AC, et al. Am J Psychiatry. 2003; 160: 533– Feltner DE, et al. J Clin Psychopharmacol. 2003; 23: 240– Pande A,C et al. Int J Neuopsychopharmacol (suppl 1) S344. Abstract P.P Rickels K, et al. Arch Gen Psychiatry. 2005; 62: 1022– Montgomery S, et al. Brit J Psychiatry. 2008; 193: 389– Feltner D, et al. Int Clin Psychopharmacol. 2008; 23: 18–28.
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7. Pregabalin-steady state
Achieved within 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

8. 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

9. Pregabalin has a unique mechanism of action for the effective treatment of GAD
Significant reduction in HAM-A scores from week 11,2
Significant improvement in both psychological and somatic symptoms at 300–600mg/day2
Anxiolytic efficacy is similar to a benzodiazepine3
Significant reduction in risk of relapse over 6 months compared with placebo4
Well tolerated, with a favourable safety profile2,5,6
Unique anxiolytic mechanism of action offering a different treatment option for GAD2,3
1. Data on file – PGB025 “PEACE Data” Pfizer Ltd. 2. Montgomery SA. Expert Opin Pharmacother 2006: 7; 2139– Rickels K, et al. Arch Gen Psychiatry 2005: 62; 1022– Feltner D, et al. Int Clin Psychopharmacol. 2008; 23: 18– Data on file – PGB023 (AE summary GAD) Pfizer Ltd. 6. LYRICA® Summary of Product Characteristics 2008.
LYG100 January 2009 9

10. Pregabalin all doses* (n=1149)
Most common adverse events and discontinuation rates with pregabalin versus placebo
Pregabalin all doses* (n=1149)
Placebo (n=484)
Adverse events (%)
Discontinuations (%)
Adverse events (%)
Dizziness
31.1
2.5
8.9
0.6
Somnolence
29.2
4.0
11.6
1.2
Dry mouth
15.1
0.3
6.4
0.0
Infection
10.2
8.1
0.2
Nausea
9.8
1.0
9.3
Amblyopia
7.5
0.9
2.1
Incoordination
7.1
Constipation
6.2
3.1
Thinking abnormal
6.1
1.1
2.3
This figure represents pooled data from six studies: all studies included a 1-week washout period then rapid escalation (1–6 days) to an assigned dose (pregabalin 150–600mg/day, BID or TID; or placebo), followed by 1-week taper after completion of the treatment1,2
All studies were double blind, fixed dose, placebo controlled and 4–6 weeks in duration. Patients met the DSM-IV diagnostic criteria for GAD and were 18 years of age1
At baseline, patients were required to have a total score 20 on the Hamilton rating scale for anxiety (HAM-A). The main efficacy measure was change from baseline to endpoint in the total score of the 14-item HAM-A1
Adverse events were typically mild-to-moderate and transient in duration1
Overall discontinuation rates owing to adverse events were 11% for pregabalin and 9% for placebo2
References
Montgomery SA. Expert Opin Pharmacother. 2006; 7: 2139–2154.
Data on file – PGB023 (AE summary GAD) Pfizer Ltd.
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.
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