1. Long-term Efficacy Data for Psychiatric Drugs Rationale for Long-Term Treatment Earl Giller, MD, PhD Pfizer Global Research & Development Long-Term Efficacy for Psychiatric Drugs Psychopharmacology Drugs Advisory Committee October 25, 2005 Long-Term Efficacy for Psychiatric Drugs Psychopharmacology Drugs Advisory Committee October 25, 2005

2. 2 Overview uTreatment duration beyond the acute episode depends on multiple factors, including diagnosis, illness course/chronicity, severity, treatment resistance, concomitant therapy and patient preference uGuideline recommendations for duration of treatment beyond the acute episode vary from months (eg first episode of MDD) to several years (eg 1 st episode of schizophrenia) to lifetime (for patients with severe recurrent episodes or chronic symptoms) uClinically relevant stabilization times differ by disorder uMost patients discontinue or switch medications well before guideline recommended durations uGiven this variability in the rationale for long-term treatment, long-term clinical trials will be different by disorder, indication and medication uTreatment duration beyond the acute episode depends on multiple factors, including diagnosis, illness course/chronicity, severity, treatment resistance, concomitant therapy and patient preference uGuideline recommendations for duration of treatment beyond the acute episode vary from months (eg first episode of MDD) to several years (eg 1 st episode of schizophrenia) to lifetime (for patients with severe recurrent episodes or chronic symptoms) uClinically relevant stabilization times differ by disorder uMost patients discontinue or switch medications well before guideline recommended durations uGiven this variability in the rationale for long-term treatment, long-term clinical trials will be different by disorder, indication and medication

3. 3 Acute, Continuation and Long-Term Treatment uMost psychiatric disorders require acute, continuation and long- term treatment uNew medications are still urgently needed for acute treatment uContinuation (maintenance) treatment prevents immediate return of symptoms (relapse) uFor many disorders, long-term treatment is also required for Prevention of new episodes (recurrence) Control of chronic symptoms not necessarily associated with an acute episode uThe majority of patients require long-term treatment, however, so the terminology of maintenance treatment to prevent relapse for most psychiatric disorders is reasonable uMost psychiatric disorders require acute, continuation and long- term treatment uNew medications are still urgently needed for acute treatment uContinuation (maintenance) treatment prevents immediate return of symptoms (relapse) uFor many disorders, long-term treatment is also required for Prevention of new episodes (recurrence) Control of chronic symptoms not necessarily associated with an acute episode uThe majority of patients require long-term treatment, however, so the terminology of maintenance treatment to prevent relapse for most psychiatric disorders is reasonable

4. 4 Different Courses of Illness by Disorder (DSM-IV) Supports Different Trials uUnipolar and Bipolar Disorder (episode = 4-6 months) Relapse: return of symptoms within episode Recurrence: return of symptoms after full remission (recovery) Recovery duration: 2-6 months Symptom worsening without full inter-episode recovery not well defined uSchizophrenia (episode length undefined) Episodic with or without inter-episode residual symptoms Full remission only after single episode uAnxiety Disorders (episode not considered) No definition of relapse/recurrence Most have a chronic, fluctuating course uLong-term efficacy study designs should differ because of disorder-specific courses of illness and treatment uUnipolar and Bipolar Disorder (episode = 4-6 months) Relapse: return of symptoms within episode Recurrence: return of symptoms after full remission (recovery) Recovery duration: 2-6 months Symptom worsening without full inter-episode recovery not well defined uSchizophrenia (episode length undefined) Episodic with or without inter-episode residual symptoms Full remission only after single episode uAnxiety Disorders (episode not considered) No definition of relapse/recurrence Most have a chronic, fluctuating course uLong-term efficacy study designs should differ because of disorder-specific courses of illness and treatment

5. 5 Episode (MDD) Multiphase Treatment “Normalcy” Symptoms Syndrome Treatment Phases Acute Continuation Maintenance Response Remission Relapse Recovery (2-6 months) Recurrence Kupfer DJ et al., 1991: J Clin Psychiatry 52:28 –34. Frank E et al., 1991: Arch Gen Psychiatry 48: 851-855 Kupfer DJ et al., 1991: J Clin Psychiatry 52:28 –34. Frank E et al., 1991: Arch Gen Psychiatry 48: 851-855

6. Mania Hypomania Euthymia Minor Depression Major Depression Preliminary Phase Preventive Phase Multiphase Treatment Approach More Complex in Bipolar Disorder Frank E et al. Biol Psychiatry. 2000;48:593-604

7. 7 Guidelines Durations of Long-Term Treatment Indication Recommended Length of Treatment MDD Continuation: 4-5 Months After Remission 1 Maintenance: Depending on risk, severity Panic Disorder 6-9 months for response and response consolidation; and 3 months for stable symptom resolution 2 PTSD Acute: 6-12 months after response; Chronic: 12-24 months after response 3 OCD 12 months 4 Schizophrenia Chronic Maintenance treatment 5,6 Stabilization: at least 6 months Stable: >1 episode Bipolar Disorder Chronic Maintenance treatment 7,8 1 Practice Guideline APA 2000; 2 APA practice guidelines for Panic Disorder, Am J Psychiatry 1998; 155 (5, suppl):1-34; 3 Foa et al. Expert Consensus Guideline series: treatment of PTSD J Clin Psychiatry 1999;60 (Suppl 16): 1-76; 4 March et al. Expert Consensus Guideline series: treatment of OCD. J Clin Psychiatry 1997 58 (suppl 4): 1-72; 5 APA 2004; 6 Robinson et al. Schizophrenia Bulletin 2005; 7 TIMA 2005; 8 Sachs et al. J Clin Psychopharmacology 1996

8. 8 0.0 0.2 0.4 0.6 0.8 1.0 060120180240300360420 0.0 0.2 0.4 0.6 0.8 1.0 060120180240300360420 Guideline Durations of Treatment Rarely Obtained in Clinical Practice: Rx Data Discontinuation Curves 0.0 0.2 0.4 0.6 0.8 1.0 06001,2001,800 Discontinuation from Treatment with 5 SSRIs Discontinuations by Antipsychotic – Schizophrenia Discontinuations by Antipsychotic – Bipolar Disorder Proportion Remaining on Treatment Days on Treatment Median = 4- 6.5 Months (Includes acute treatment) Median = 3- 4.5 Months Verispan Persistency & LOT Analysis, July 2005 (class of antidepressants); Verispan Persistency & LOT Analysis, July 2004 (class of antipsychotics) Clinically relevant stabilization period about 2-3 months Patients remaining after 6 months are small minority Clinically relevant stabilization period about 2-3 months Patients remaining after 6 months are small minority

9. 9 Source: Lieberman et al., N Engl J Med 2005; 353:1209-23 Guideline Durations of Treatment Rarely Obtained in Clinical Practice: CATIE Schizophrenia Study Discontinuation Curves Proportion of Patients Without Event 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0369121518 Time to Discontinuation for Any Cause (Mo)

10. 10 Conclusions uClinically relevant stabilization time is about 2-4 months because of discontinuation rates in clinical practice and trials uRegulatory requirements for long-term treatment data should be flexible because the type, extent and timing of long-term clinical studies differs by indication, type of medication and existing data for the medication and class uExpert consensus workgroups should be convened to develop guidelines for appropriate study designs for long-term efficacy data for each indication uClinically relevant stabilization time is about 2-4 months because of discontinuation rates in clinical practice and trials uRegulatory requirements for long-term treatment data should be flexible because the type, extent and timing of long-term clinical studies differs by indication, type of medication and existing data for the medication and class uExpert consensus workgroups should be convened to develop guidelines for appropriate study designs for long-term efficacy data for each indication