This document provides an overview of aripiprazole for the treatment of schizophrenia. It discusses: 1. The history of antipsychotic medications and the limitations of typical antipsychotics that led to the development of atypical antipsychotics like aripiprazole. 2. Aripiprazole's unique receptor binding profile as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, which allows it to control positive and negative symptoms with a low risk of extrapyramidal side effects. 3. Clinical trial evidence demonstrating aripiprazole's efficacy in treating schizophrenia, including improvements in symptoms and functioning, and a better side effect and tolerability profile compared to

1. Aripiprazole in
Schizophrenia
1

2. The Impact of Schizophrenia on Overall
Functioning
2

3. Dopamine-serotonin system
stabilizer: aripiprazole
’30s ’40s ’50s ’60s ’70s ’80s ’90s ’00 ‘05
ECT
Chlorpromazine
Thioridazine
Trifluoperazine
Fluphenazine
Perphenazine
Haloperidol
Loxapine
Typical
antipsychotics
Atypical
antipsychotics
Clozapine
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Developments in Antipsychotics
3

4. • Anticholinergic
• Extrapyramidal
• Sedation
• Cardiovascular
• Metabolic
• Altered hormones
• Lowered seizure
threshold
• Cognitive
function
• Negative
symptoms
• Depressive
symptoms Gaps in
Efficacy
Profound
number
of side-
effects
Non-
adheren
ce &
complian
ce
Co-
morbiditi
es
Limitations of Current Antipsychotics
4

5. Effect and side effects of typical antipsychotics
Pathways DA level in
patients
with
Schizo-
phrenia
Effect of
DA on Pt
Action
required
Typical
Anti-
psychotic
Effect & Side-effects
of typicals
Mesolimbic High +ve
Sympto
ms
Reduce
the level
of DA
D2
blockade
Reduced +ve
symptoms
Mesocortic
al
Low -ve
Sympto
ms
Increase
the level
of DA
D2
blockade
Increased –ve
symptoms (Makes
patient quiet)
Nigrostriat
al
Normal Nil Nil D2
blockade
EPS (Extra Pyramidal
Symptoms) AE
TuberoInfu
ndibular
Normal Nil Nil D2
blockade
Hyperprolactinemia
AEs (Galactorrhea/
Gynecomastia)
Robinson DS. Antipsychotics: Pharmacology and Clinical Decision Making. Primary Psychiatry. 2007;14(10):23-25
5

6. The goal is to get the patients well and to keep them well.
An Ideal
Antipsychotic
Well tolerated
No EPS/ No TD
Improves
quality of life
& social
functioning
Improves
cognitive
functions
Improves
positive,
negative &
mood
symptoms
Easy to use –
dosing,
switching,
titration
What Constitutes an Ideal
Antipsychotic
6

7. Ineffective
34%
Weight gain
34%
Dizziness
7%
Sedation
7%
Other
18%
Ineffective
23%
EPS/Akas
21%
Tremors
10%
Sedation
9%
Sexual
Dysfunction
9%
Insomnia
8%
Other
20%
Olanzapine Risperidone
Reasons for Switching
Scott Levin PDDA, June 2001
pg7

8. Dopamine-serotonin antagonism - the theory
behind Atypical Antipsychotics
Dopamine receptor blockade reversed by serotonin receptor
blockade in Nigrostriatal dopamine pathway
Stahl SM. Prim Care Companion J Clin Psychiatry 2003. 5(1):9-13 8

9. The dopamine hypothesis of
schizophrenia
9

10. Intrinsic Activity at D2 Receptors
Intrinsic Activity Describes the Ability
of a Compound to Activate Receptors
No activation
Antagonist (haloperidol, etc)
Partial activation
Partial agonist (aripiprazole)
Full activation
D2 receptor
Full agonist (dopamine)
*
10

11. Dopamine Partial Agonism:
Positive Symptoms and EPS
Improvement of
positive symptoms
No EPS
No
hyperprolactinemia
DA
stabilization
pg11

12. Dopamine Partial Agonism:
Negative Symptoms
Stabilized
signal Improvement of
negative symptoms, cognition
and amotivation pg12

13. Aripiprazole: A unique atypical
Antipsychotic
13

14. •Decreased
propensity for
orthostasis,
sedation &
weight gain)
•No antimuscarinic
side-effects such
as dry mouth,
thirst, blurred
vision, dry skin,
increased heart
rate)
• Improves
positive and
negative
symptoms
• Reduced risk of
EPS
•Functional antagonist
under conditions of
dopamine hyperactivity
control positive
symptoms)
•Functional agonist
under conditions of
dopamine hypoactivity
control negative,
cognitive & causes
minimal motor effects
Partial
agonist
at D2
receptors
High-
affinity
binding to
5-HT1A
and 5-
HT2A
Low-to-
moderate
affinity at
α1 and H1
receptors
No affinity
for
muscarinic
receptors
Unique Receptor binding profile
14

15. 100 nM DA
+ haloperidol
100 nM DA
+ aripiprazole
Partial agonism
Full blockade
Blocking,
partial activation
Concentration (M)
10-10 10-9 10-8 10-7 10-6 10-5
0
50
100
Aripiprazole Is a Partial Agonist at
Cloned Human D2 Receptors
%
Max.
response
Data on file
Receptor blockade needed
for clinical response
pg15

16. FDA approval history of Aripiprazole
Indication Year of Approval
Treatment of schizophrenia in adults November 2002
Treatment of acute bipolar mania, including manic and
mixed episodes associated with bipolar disorder
September 2004
For maintaining efficacy in patients with Bipolar I Disorder
with a recent manic or mixed episode who had been
stabilized and then maintained for at least six weeks.
March 2005
Treatment of schizophrenia in adolescents aged 13-17
years
November 2007
Add-on for major depressive disorder November 2007
As an adjunct to lithium or valproate for acute treatment
of manic or mixed episodes associated with bipolar I
disorder
May 2008
Treatment of irritability associated with autism spectrum
disorder in children aged 6 to 17 years.
November 2009
As an adjunct to lithium or valproate for maintenance
treatment of bipolar I disorder
February 2011
16

17. Benefits of receptor binding profile of Aripiprazole
Receptor Affinity of
Aripiprazole
Effect
D2 High  Controls acute psychosis
5-HT 1A High  Increases dopamine release & thus
causes:
o Improvements in cognition &
negative symptoms
o Reduces risk of EPS
 Antidepressant and anxiolytic effects
5-HT2A High  Improves negative symptoms and
diminish the risk of EPS
Inhibition of
serotonin
transporters
Moderate  Antidepressant activity
Alpha1 Moderate  Low risk of orthostatic hypotension and
appetite-stimulation
H1 Moderate  Low risk of weight gain and sedation
Cholinergic
muscarinic
receptors
No  No anti-cholinergic side effects (blurred
vision, dry mouth, GI irritation)
CNS Drug Rev. 2004 Winter;10(4):317-36
17

18. Pharmacokinetics of Arip-MT
Mean peak plasma levels 3 to 5 h
Bioavailability 87%
Protein Binding >99%
Metabolism Liver, cytochrome P450 3A4
and 2D6 systems
Steady State 2 weeks
Half-life 75 h (Active metabolite 95 h)
Excretion Feces and urine
CNS Drug Rev. 2004 Winter;10(4):317-3618

19. Clinical Evidences
19

20. BETA trial
Objective:
 To evaluate the overall effectiveness of aripiprazole in patients
with schizophrenia or schizoaffective disorder treated in a general
psychiatry outpatient practice setting.
Method:
 8-week, multicenter, open-label study
 1599 outpatients with schizophrenia or schizoaffective disorder
were randomly assigned to receive either aripiprazole (n =1295)
or another antipsychotic medication (safety control [SC] group n
=304).
 Aripiprazole was initiated at 15mg/d with the option to adjust
between 10–30mg/d.
20

21. BETA trial proved Arip as most effective
drug for schizophrenia
54% and 69% of response rate with Aripiprazole at week 8 21

22. Preference of medicine ratings, BETA
TRIAL
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Week 1 Week 8 Week 1 Week 8
Aripiprazole Safety Control
49%
86%
42%
57%
42%
72%
33%
45%
Preference
of
medicine
ratings
%
Patient Caregivers
Aripiprazole was most preferred drug by both patients and
caregivers in comparison to their pre-study medication
22

23. •Aripiprazole showed improvement in overall
psychopathology at week 1 which continued
throughout the 8-week treatment phase
23

24. In the acute treatment of adolescents with schizophrenia
Graph 4. Change in Total Score on the Positive and Negative Syndrome
Scale for Adolescents with Schizophrenia in a Placebo-Controlled Trial
of Aripiprazole
•6-week multicentric, double-blind, randomized, placebo-controlled trial
•13 to 17 years old subjects with a DSM-IV diagnosis of schizophrenia
24

25. Treatment with both doses of Aripiprazole resulted in
significantly higher rates of remission at week 6
High Remission Rate with Aripiprazole in patients
with Schizophrenia
25

26. •Both 10- and 30-mg/day doses of aripiprazole were superior to
placebo in the acute treatment of adolescents with schizophrenia.
•Aripiprazole 10 & 30 mg/day produced:
•Improvement in positive symptoms
•Improvement in Negative symptoms
•Faster onset of action as early as week 1
•High remission rate
26

27. Schizophrenia Trial of Aripiprazole (STAR) study
Eur Psychiatry. 2007 Oct;22(7):433-43
27

28. STAR study
•26-week, multicentre, randomized, naturalistic, open-label study.
IAQ: Investigator Assessment Questionnaire 28

29. Graph 8. CGI-I response rate (LOCF) at Week 26 controlling for
prior antipsychotic medication and country
29

30. Conclusion
Aripiprazole treatment was associated with significantly better
effectiveness compared with SOC treatment. The effectiveness was
supported by:
oLower IAQ scores
oSuperior CGI-I responder rate
oImprovement in quality of life scale scores
A greater proportion of patients and caregivers rated Aripiprazole
as “much better” than their previous medication compared with the
group treated with SOC.
30

31. Aripiprazole equiefficacious to Olanzapine
•52-week, open-label extension to a 26-week, multicenter, randomized, double-
blind, and placebo controlled trial in patients with chronic schizophrenia
•Aripiprazole (15–30 mg/day, n=104) or olanzapine (10–20 mg/day, n=110)
Psychopharmacology (Berl). 2006 Dec;189(2):259-66. 31

32. Conclusion:
Aripiprazole equiefficacious to Olanzapine
Aripiprazole showed similar efficacy to olanzapine for the
treatment of schizophrenia patients with chronic, stabilized illness
Both maintained symptom control, providing similar, modest
improvements in efficacy scores over the 52-week study.
Sustained Efficacy
Among the patients experiencing acute relapse of schizophrenia,
both treatment provided similar, sustained improvements in
symptom scores over 52-week.
Psychopharmacology (Berl). 2006 Dec;189(2):259-66. 32

33. Relapse prevention outcome
Graph 11. Time from Randomization to relapse
33

34. •58.8% of patients receiving Aripiprazole continued the treatment at endpoint
compared to 38.1% with placebo (p < 0.001) 34

35. Aripiprazole Long-Term Trial 2
Time to Discontinuation Due to Lack of Efficacy
or Adverse Events
PROPORTION
OF
PATIENTS
ARIP-30MG
HALO-10MG
Days in Study
p-value < 0.0001
0 100 150 250 300 350
200
50
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
*
pg35

36. Aripiprazole Neurocognitive Function Trial:
Comparison With Olanzapine (cont’d)
*
0.25
0.20
0.15
0.10
0.05
0 0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Aripiprazole (n=76)
Olanzapine (n=93)
P<0.05
P<0.05
*
*
*Significant improvement from baseline (P<0.05). LOCF analysis, based on the California Verbal Learning
Test and the Continuous Performance Test - Identical Pairs version.
Cornblatt et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S185.
Cognitive Ability Verbal Learning
*
Better
Aripiprazole (n=76)
Olanzapine (n=93)
Week 8 Week 26 Week 8 Week 26
pg36

37.  QTc interval (>450
msec) occurred in 1
patient treated with
placebo, 2 patients
treated with
haloperidol, and in 2
patients treated with
aripiprazole
 No patient had a QTc
interval of >500 msec
*QTc interval determined by Fractional Exponent Correction Method (FDA).
†P0.05, significantly different from placebo.
Mean
change
from
baseline
(msec)
Placebo
-3.56
Haloperidol
-0.62
All aripiprazole
-4.16
-4
-2
0
2
4
6
-6
Aripiprazole Short-Term Clinical
Trials: Mean Change in QTc Interval*
†
*
pg37

38. Aripiprazole Long-Term Trial 1:
Effects on LDL, HDL, and Triglyceride Levels
-14
-12
-10
-8
-6
-4
-2
0
2
4
LDL HDL Triglycerides
Median
change
from
baseline
(mg/dL)
Placebo
Aripiprazole
Data obtained from fasted plasma samples.
Data on file.
n = 119/116 120/116 120/116
*
pg38

39. *P<0.01 vs change with placebo.
All patients but one remained within normal limits.
Stock et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S185.
Serum Prolactin Levels: Pooled Data From
Aripiprazole Short-Term Clinical Studies
0
5
10
15
20
25
Placebo Haloperidol Aripiprazole
Baseline
LOCF
 0%
 120%*
 57%*
Median Serum Prolactin Levels at Baseline and End Point
Serum
prolactin
(ng/mL)
n = 339 185 729
*
pg39

40. Safety and Tolerability
CNS Drug Rev. 2004 Winter;10(4):317-36
40

41. 41

42. Strategies for switching from another antipsychotic agent to Aripiprazole
in the outpatient setting a
Time Aripiprazole
dose
Previous medication
dose
Aripiprazole dosage
variation
Starting dose 10–15 mg/day Maintain dose -
End week 2 10–15 mg/day Reduce by about 50% Dose may be reduced to
10 mg/day if tolerability
problems arise
End week 4 10–30 mg/day Reduce by about 50% 15 mg/day is the
maintenance dose; very
few patients may need to
increase to 30 mg/day;
dose may be reduced to 10
mg/day if tolerability
problems arise
a Benzodiazepine or antihistaminic or anticholinergic drugs may be added to
aripiprazole in order to control rebound effects due to the discontinuation of
medications with high antihistaminic or anticholinergic properties.
Clin Drug Invest 2007; 27 (1): 1-13
42

43. Suggestions for the management of concomitant symptoms and adverse effects in
patients with schizophrenia treated with aripiprazole
Symptom Management
Agitation Benzodiazepines (lorazepam) or
Anticholinergic drugsa or
Antihistaminic drugsa (e.g.
diphenhydramine) or
Valproic acid or Gabapentin
Nausea Administer aripiprazole with a meal or
Reduce aripiprazole dose or
Add an antiemetic (only if above measures fail)
Insomnia Add an hypnotic agent during the first days of treatment
Administer aripiprazole in the morning
Divide dose of aripiprazole into two daily half doses (am and pm)
Akathisia Reduce dose or
Benzodiazepines or
β-Adrenoceptor antagonist (propranolol) or
Gabapentin or
Anticholinergic agent
a Consider previous antipsychotic withdrawal after switching
antipsychotic agents and use antihistaminic or anticholinergic drug as appropriate.
43

44. Arip-MT –
at a Glance
Unique
receptor
binding
Profile
Faster
onset of
action as
early as
week 1
Equiefficac
ious to
olanzapine
Reduces
positive &
negative
symptoms
No
adverse
metabolic
changes
Prevents
relapse
Most
preferred
drug by
both
patients &
caregivers
44

46. 46