# Presentation: 702774

## Alan Breier, M.D.

**Leader, Zyprexa Product Team**
**Lilly Research Fellow**
**Professor of Psychiatry, **
**Indiana University School of Medicine**
**Adjunct Associate of Psychiatry, **
**University of Maryland School of Medicine**

**Lilly Research Laboratories**
**A Division of Eli Lilly and Company**

## Alzheimer's Disease

**Major Public Health Priority**

**4.5 million US citizens affected - numbers dramatically rising with aging population**
**Massive human suffering - patients and families**
**$80-$100 billion per year in total treatment costs**
**	****	****- $213,000 per family treatment costs**
**>50% have psychosis and/or behavioral disturbances**
**	****	****- major precipitant for institutional care**
**Neuroleptics commonly used off-label**
**	****	****- currently insufficient FDA direction to prescribers**
**	****	****- high rate of adverse events, e.g., EPS, TD, excessive ****	****	****	****sedation**

## Antipsychotic Drug Use in the Elderly (>65 yrs.)

**US Experience (1998-1999)**

**Dementias****	****14.7****	****  30%**
**Depression****	****10.4****	****  21%**
**Schizophrenia****	****  8.8****	****  18%**
**Bipolar****	****  4.7****	****    9%**
**Other****	**_**11.2**_**	****  **_**22%**_
**Total****	****50.0****	****100%**

**Source:  IMS: Medical MIDAS Moving Annual Total Q399**

**Days of Therapy**
**(in millions)**

## Challenges

**Urgent need to establish clear guidelines for drug approval**
**	****  ****-  each month:  20,000 new AD cases**
**	****	****	****          ****$5.7 billion in treatment costs**
**Strike the correct balance between appropriate clinical nosology and accelerating drug development**
** ****	****  ****- 3-4 years for new registration trials and approval**
**	****  ****- Data from existing controlled trials could expedite **
**	****     ****approval and appropriate labeling**

## Psychosis Associated with Alzheimer's Disease

**Support for a Distinct Indication**

**Clinical features (symptoms, course) are specific to AD**
**Clinical presentation is readily recognized by clinicians and operationally defined by validated rating instruments**
**May represent a distinct AD subgroup**
**Antipsychotic drug response may be specific to AD**

## Psychosis Associated with Alzheimer's Disease

**Essential Diagnostic Criteria**

**  ****Diagnosis of dementia of the Alzheimer's type (DAT)**
**  ****Prominent delusions and/or hallucinations**
**	****	****- severity e.g., causes impairment/distress**
**	****	****- persistence**
**Psychotic symptoms not due to other medical conditions, delirium or Axis I disorders**

## Psychosis Associated with Alzheimer's Disease

**DSM-IV Provides a Diagnostic Approach**

**  ****The essence of DSM-IV ****(Introduction, Page 23)**
**	****	****- diagnosis based on clinical judgement and symptom****	****	****	****	****persistence and severity**
**Psychosis associated with Alzheimer's disease**
**	****	*****- diagnostic criteria for DAT with delusions (290.12, 290.20)***
***	******	******- diagnostic criteria for psychotic disorder due to***
***	******	******   ******AD with hallucinations (293.82)***

## DSM-IV Diagnosis of  Psychosis Associated with Alzheimer's Disease

**Patient meets diagnostic criteria for dementia of the Alzheimer's type**
**Psychotic symptoms are not due to other medical conditions or Axis I disorders**
**Delusions are the predominant feature: 290.12 or 290.20**
**Hallucinations are the predominant feature: 293.82**
**Validated rating instruments (e.g., NPI, BEHAVE-AD) may be used to further characterize psychotic symptoms**

## Behavioral Disturbances of Alzheimer's Disease

**Acute agitation**
**Aggression**
**Sleep Disturbances**
**Anxiety**
**Depression**

## Common features across a number of disease states  - a behavioral syndrome comprising hostility, tension, uncooperativeness, poor impulse control, and/or excitement
Strong face validity and reliability
Causes significant adverse impact on patients
Commonly warrants pharmacological intervention

**Strong face validity and reliability**
**Causes significant adverse impact on patients**
**Commonly warrants pharmacological intervention**

**Acute Agitation**

## Acute Agitation

**Support for a Broad Indication**

**Not unique or specific to AD - core clinical characteristics are relatively similar across disease states**
**Consistent with the regulatory models of pain and fever**
**Indication should be supported with data from a number of different disease states**

## Acute Agitation

**Assessment Approach for Registration Trials**

**Abrupt onset of agitation: poor impulse control, uncooperativeness, hostility, tension, and/or excitement**
**Sufficient intensity and severity - requires treatment and/or results in impairment/distress**
**Validated rating instruments may be used to characterize severity and phenomenology**

## Acute Agitation

**	****-  high face validity (items: poor impulse control, tension,**
**	****   ****hostility, uncooperativeness, excitement)**
**	****-  factor analysis (Kay & Sovy, 1990; Lancon 1998); **
**	****   ****further validated by Lilly in agitated and non-agitated**
**	****   ****patients**
**  ****Other validated instruments (examples) **
**	****-  Cohen-Mansfield Agitation Inventory - validated in**
**	****    ****patients with dementia**
**	****-  Corrigan Agitated Behavior Scale - used in clinical trials**
**	****    ****of acute agitation in schizophrenia, ER setting**

**Acute Agitation**
**Validated Rating Instruments**

## Conclusion

**Urgent need to develop new therapeutics for AD patients with psychosis and behavioral disturbances **
**Psychosis associated with AD warrants a distinct indication**
**Diagnostic approaches available now for registration trials of psychosis associated with AD**
**Acute agitation is a non-specific behavioral syndrome that warrants a broad indication across many diseases**