Transcript Akathisia

Effectiveness of Aripiprazole in
Patients with Schizophrenia
A Focus on Acute Treatment
金哲應(仁荷大學病院)
Schizophrenia(調鉉病) ?
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Genetic predisposition likely establishes a psychosis
“threshold”; subject to environmental factors
Etiology unknown; abnormal neuronal circuitry
e.g., cortico-limbic-thalamic, is suspected
• Implicates multiple CNS neurotransmitters
• Incidence of 1% worldwide
Early age of onset (15-25 years) and a chronic,
relapsing course are common
Schizophrenia(調鉉病)
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Lifelong disabling psychiatric disorder
Severe & variable symptoms
: positive, negative symptoms, cognitive
deficits, depressive symptoms.
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At present, NO CURE ,but Manageable
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Vital Statistics in Schizophrenia
• 1% prevalence worldwide
• Impaired functioning and disability
• Old studies : 20% shorter life expectancy
• New studies: 30-40% reduction in potential lifeyears
• Higher suicide risk(10%5.6%(Palmer et al 2005)
• Higher all-cause mortality
APA2007, Nasrallah HA
5/80
Evolution of treatments for
schizophrenia
Impact of treatment services on proximal and
distal outcomes in schizophrenia
Developments in Medical Treatments for
Psychotic Disorders
‘30s
‘40s
ECT
Reserpine
Typical
Antipsychotics
‘50s
‘60s
‘70s
Haloperidol
Fluphenazine
Thioridizine
Loxapine
Perphenazine
Chlorpromazine
‘80s
‘90s
‘00
Clozapine
Risperidone
Olanzapine
Quetiapine
Atypical
Antipsychotics
Ziprasidone
Aripiprazole
The Next-generation
Atypical Antipsychotic
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The 3 Phases of Drug Treatment
Phases of treatment
•
Administered during the period
from the beginning of a
psychotic episode to a clinical
response, ideally remission1
Continuation
•
Ongoing treatment of the
psychotic episode from the point
of clinical response to the point
of recovery1
Maintenance
•
Optimize protection against the
recurrence of episodes1
•
Frequency and number of
episodes can be reduced with
maintenance therapy2
Acute
Continuation
=
Maintenance
1. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press;2007.
2. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium
treatment. J Clin Psychiatry. 2002;63:5–12.
Treatment goals of Schizophrenia by Phase
Behavior control
Efficacy
Sedation
Diagnosis
Non-specific?
Safety & Tolerability
1~2 days
Acute EPS
-Dystonia
-Akathisia
Symptom control
Positive symptom control
Agitation control
- Aggressive behavior
- Violent behavior
- Hostility
1~2 weeks
EPS
Stabilize positive symptom
Negative symptom control
Affective symptom control
Cognitive functioning
Physical functioning for recovery
3 month
6 month
Relapse prevention
Stabilize positive symptom
Negative symptom control
Affective symptom control
Cognitive functioning
Physical functioning for recovery
1~2 years
TD
Weight gain
Cardiometabolic disturbance
Prolactin elevation
Sedation disturb functioning
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Acute Phase of Treatment
• Goals
- Develop alliance with the patient and family
- Prevent harm
- Control disturbed behavior
- Reduce the severity of psychosis and associated
symptoms(eg, agitation, aggression, negative
symptoms, affective symptoms)
• Pharmacotherapeutic interventions
• Weeks to months
Limitation of Typical & Atypical
Antipsychotics (except Abilify)
• Mechanism of Action
– Dopamine antagonists
• Efficacy
– Inadequate response of negative and cognitive symptoms
• Safety & Tolerability
– Pervasive side effects
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•
•
•
•
•
Weight gain
Diabetes
Dyslipidemias
Anticholinergic side effects
Sedation
Hyperprolactinemia
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Efficacy vs Effectiveness
• Efficacy : how well a medication works
as established through rigorous &
controlled clinical investigation
• Effectiveness : usefulness of a
medication under conditions of actual
clinical practice
Effectiveness= Efficacy+Tolerability+
Adherence+Ease of use
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Abilify는?
Unique MOA(SDADSS)
Partial Agonist
Sedation
효능 : Efficacy & Effectiveness
안전성 : 대사장애, 체중증가, 고프로락틴
유발 위험 없다.
• 다양한 적응증
•
•
•
•
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Aripiprazole and Dopamine Partial Agonism
• Aripiprazole is a high-affinity D2 partial agonist
– Functional antagonist under conditions of dopamine hyper
activity in limbic cortex (i.e., helps in control of positive
symptoms)
– Functional agonist in conditions of dopamine hypoactivity
in prefrontal cortex and basal ganglia (ie, control of negati
ve symptoms, cognitive improvement, minimal motor effe
cts)
Dopamine system stabilizer
Burris et al. J Pharmacol Exp Ther. 2002;302:381.
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Aripiprazole Pharmacology
related to Serotonin Rc
• Abilify also has a partial agonism effect at 5-HT1A
receptors. 5-HT1A receptors is associated with
improvements in anxiety, depression, cognitive and
negative symptoms, and decreased risk of EPS. 5HT1A agonism also regulates D2 dopamine.
• 5-HT2A antagonism allows these medications to have
anti-depressant efficacy as well as reduces reliability
for EPS by regulating dopamine itself.
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Aripiprazole Activity at Receptors
Associated To Its Side Effects
• Moderate-low affinity at 1 and H1;
no affinity for muscarinic receptor subtypes
• Potential clinical impact
– Low propensity for orthostatic hypotension
(1-adrenergic receptors)
– Low liability for weight gain and
somnolence
(H1 histamine receptors)
– Low potential for cognitive impairment
(muscarinic cholinergic receptors)
Data on file.
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US FDA Approval (AbilifyTM)
• 2002.11 : Schizophrenia
• 2003. 09 : Maintenance therapy, Sch.
• 2004.10 : Acute Bipolar mania, including manic
& mixed episode
• 2005. 03 : Maintenance therapy, Bipolar
• 2007. 11 : Adolescent schizophrenia ( 13~17
year)
• 2007.11 : Add-On Treatment of MDD
•
Tourette
•
Abilify Injection : Agitation ass. With schizophrenia
or bipolar disorder, manic or mixed
* Bipolar Dep, PTSD(Anxiety), OCD(add on), Anhedonia ?
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REAL WORLD CONSIDERATION
OF ACUTE MANAGEMENT
Issues of Abilify Starting
• Acute management
– Starting dose
- 10~20mg starting
- for inadequate response : inc dose as quickly as
possible
- for sedation : use BZ at a full dose in concomitant
therapy
– Activation issue associated with dose in acute phase
- generally, activation occurs at a low dose
- to manage activation, inc dose or use BZ
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Aripiprazole, Ziprasidone, and Quetiapine
in the Treatment of First Episode
Nonaffective Psychosis
Crespo-Facorro B et al. J Clin
Psychopharmacol 2013;33:215-220
Clinical Efficacy
• Rate of Responder
- Ari : 63.6%, Zip : 42.0%, Quet : 46.2%
(p=0.047)
• Adverse Events
1) somnolence : Ari 21.2%, Zip : 40.0%, Quet :
45.0%(p=0.020)
2) Akathisia : Ari : 22.7%, Zip 16.0%, Quet :
2.5%(p=0.020)
The efficacy of aripiprazole in the treatment of
multiple symptom domains in patients with
acute schizophrenia: A pooled analysis of data
from the pivotal trials
John M. Kane a,⁎, Sheila Assunção-Talbott b, James M. Eudicone b, Andrei Pikalov c,
Richard Whitehead c, David T. Crandall b
a The Zucker Hillside Hospital, New York, NY, USA
b Bristol-Myers Squibb, Plainsboro, NJ, USA
Schizophrenia Res. 2008;105:208-215
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Changes in PANSS total score &
Subscale scores
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PANSS Positive Items
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PANSS Negative Items
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PANSS General Psychopathology Items
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Olanzapine versus Aripiprazole for
the treatment of Agitation in
Acutely ill patients with
Schizophrenia .
J Clin Psychopharmacol 2008;28:601-607.
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Study Design
• 5-day, randomized, double-blind trial
• Ho : Owing to its pure antagonist
activity, olanzapine would be superior
to aripiprazole in reducing agitation
and positive symptoms early in the
treatment of acutely ill patients.
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PANSS-EC Score Change
-2
Olanzapine
Aripiprazole
-4
-6
-8
-10
Visit 2
Visit 3
Visit 4
Visit 5
p=0.103
p=0.531
p=0.671
p=0.851
Between treatment p-value from repeated measures ANOVA model:
Change baseline score + treatment + visit + investigator + visit treatment + visit b
aseline score.
Kinon, 2008
Metabolic Parameters
Olanzapine
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30
Aripiprazole
20
p=0.030
10
80
p<0.001
60
25
0
20
-10
40
p<0.001
15
-20
10
20
5
-30
0
-40
Glucose (mg/dL)
0
Prolactin (μg/L)
Triglycerides (mg/dL)
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Kinon, 2008
Akathisia concern with Abilify
• About 10~20% of patients(3~5%)
• Generally mild to moderate in intensity
• Treat as you would with other antipsychotics
– Consider dose reduction
– Treat with beta blockers
• Not generally associated with
discontinuation
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Evaluation of Akathisia
A Post hoc Analysis of Pooled Data
Kane JM et al.
J Psychopharmacol
2010;24:1019-1029.
Akathisia
• No consensus diagnostic criteria
• DSM(APA 1994) :
- medication-induced movement disorder that is
characterized by motor restlessness accompanied by
increased nervous and restless movement
• Subtypes :
1) withdrawal
2) acute
3) tardive akathisia
• BARS(Barnes Akathisia Rating Scale)
Akathisia, Agitation, Activation, and
Aggravation
Akathisia
Agitation
Activation
Aggravation
Concentration
NO
Yes
Yes
No
Control
No
Yes
Yes(?)
No
APs
Worsen
Improve
Improve
Improve
Antiparkinson
Drug
Imp
No response
No
Response
No response
Symptoms
Motor
psychosis
Psychomotor
psychomotor
Ego-tonicity
Dystonic
Dystonic
Syntonic
Syn- or dystonic
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Summary - Results
• Akathisia with Aripiprazole
-
occurred early in treatment
mild to moderate in severity
led to few study discontinuations
did not compromise therapeutic efficacy
Proposed strategies for successful
clinical management with Aripiprazole
Mago R. Expert Opinion
Pharmacother 2008;9:1279-1290
General Issues related to Dosing
• Lack of sedation = lack of efficacy
• Agitation  BZ
• AE = mild to moderate, transient in nature ;
waiting, dosage modification, or adjunctive
medication
• Long-term benefits outweigh the short term
adverse effects
Dosing Strategies(Expert Opinion)
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Clinical Factors
Rapid/High-dose Slow/Low-dose
Patients
Illness
Treatment
Others
younger
healthy
motivated for tx
acute exacerbated
agitated
inpatient
tolerating Aps
good support
older
medical co-morbid
ambivalent
stable sx
calm
outpatient
drug naïve, intoler
limited support
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Proposed Initiation/Dosing
Strategies
Rapid/High-dose
Starting D
Target
Speed
Slow/Low-dose
Taper period
20mg
30mg
immediate
observe safety/se 2nd day
increase or decrease
4-8 weeks(clo, olan 12weeks)
Worsening
inc dose or add on
5mg
10mg
1 week
begin tapering
when target dose
reached
incr dose
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Factors Modifying Dosing
Strategies
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•
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Treatment naïve ; half dose(10mg)
Age : <18 or >65 ; quarter dose(5mg)
Medical morbidity ; half or quarter dose
Concommitant medications
- fluoxetine/paroxetine ; half dose
- carbamazepine ; twise the dose
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Management of adverse events
with Aripiprazole
 Akathisia ; BZ(clonazepam 0.5~1mg, bid or qid),
beta-blocker(30-120mg), reduce dose first &
medication
 Anxiety/agitation ; BZ(lorazepam 0.5~1mg, qid)
 Sedation/somnorance ; wait & changed to bedtime
dose reduce the dose
 Insomnia ; morning dose with food & add
hypnotics
 Nausea/vomiting ; food, reduce dose, bed time,
dividing dose
 EPS ;
 Worsening symptoms
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Summary : Abilify – Acute Tx.
• Behavior control
- Separate sedation issue from acute efficacy
- Just for 3-5 days issue
- Benzodiazepine concomitant therapy with
Abilify
- Strong sedative agent is alternative for some
patients
• Symptom control
- Very efficacious on positive symptom
- Comparable efficacy to Risperidone,
Olanzapine
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Conclusions(1)
• Clinically relevant differences exist among
atypicals in their propensity to cause AE
- Sedation, Prolactin elevation, Weight
gain & other metabolic effects
 Sedation, Metabolic & Sexual issues :
QoL, Medication adherence  Improved
Outcome
 Aripiprazole : effective as other SDA, but
minimal adverse effects.
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Conclusions(2)
 Paradigm Shift
- DA Antagonist Partial DA Agonist
- Sedating Non-sedating Agents
 Enhancing Physical Health
- Metabolic Syndrome & - Sexual Dysfunction
 Balancing Mental & Physical Health Imp QoL
& Promoting Community Reentry
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多 謝 !!
Thank You for Your Time
and Attention !!
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