Effectiveness of Aripiprazole in Pa-tients with Schizophrenia

A Focus on Acute Treatment

金哲應 ( 仁荷大學病院 )

Schizophrenia( 調鉉病 ) ? 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, relaps-ing course are common

Schizophrenia( 調鉉病 ) Lifelong disabling psychiatric disorder

Severe & variable symptoms : positive, negative symptoms, cogni-

tive deficits, depressive symptoms.

At present, NO CURE ,but Manageable

4

5/80

Vital Statistics in Schizophre-nia• 1% prevalence worldwide• Impaired functioning and disability• Old studies : 20% shorter life ex-

pectancy• New studies: 30-40% reduction in po-

tential life-years• Higher suicide risk(10%5.6%(Palmer

et al 2005)• Higher all-cause mortality

APA2007, Nasrallah HA

Evolution of treatments for schizophrenia

Impact of treatment services on proxi-mal and distal outcomes in schizophre-

nia

8

‘30s ‘40s ‘50s ‘60s ‘70s ‘80s ‘90s ‘00

Haloperidol FluphenazineThioridizine

LoxapinePerphenazine

ECT

Chlorpromazine

Typical Antipsychotics

The Next-generation Atypical Antipsychotic

Aripiprazole

ZiprasidoneAtypical Antipsychotics

Clozapine

Risperidone Olanzapine Quetiapine

Developments in Medical Treatments for Psychotic Disorders

Reser-pine

The 3 Phases of Drug Treatment

• Optimize protection against the recurrence of episodes1

• Frequency and number of episodes can be reduced with maintenance therapy2

Maintenance

• Ongoing treatment of the psychotic episode from the point of clinical response to the point of recovery1

Continuation

• Administered during the period from the beginning of a psychotic episode to a clinical response, ideally remission1

Acute

Continuation = Maintenance

Phases of treatment

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

10

Efficacy

1~2 days 1~2 weeks 3 month 6 month 1~2 years Safety & Tolerability

Diagnosis Non-spe-

cific?

Acute EPS -Dystonia -Akathisia

Behavior control Symptom con-trol

Positive symptom controlAgitation control - Aggressive behav-

ior - Violent behavior - Hostility

Stabilize positive symptom Negative symptom controlAffective symptom control Cognitive functioning Physical functioning for re-

covery

Stabilize positive symptom Negative symptom controlAffective symptom control Cognitive functioning Physical functioning for re-

covery

Relapse preven-tion

TDWeight gain Cardiometabolic distur-

bance Prolactin elevation

EPS

Seda-tion

Sedation disturb function-ing

Acute Phase of Treatment• Goals - Develop alliance with the patient and family - Prevent harm - Control disturbed behavior - Reduce the severity of psychosis and associ-ated symptoms(eg, agitation, aggression, negative symptoms, affective symptoms)• Pharmacotherapeutic interventions• Weeks to months

13

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

• Weight gain• Diabetes• Dyslipidemias• Anticholinergic side effects• Sedation• Hyperprolactinemia

14

Efficacy vs Effectiveness• Efficacy : how well a medication

works as established through rigorous & controlled clinical in-vestigation

• Effectiveness : usefulness of a medication under conditions of actual clinical practice

Effectiveness= Efficacy+Tolerability+

Adherence+Ease of use

Abilify 는 ?• Unique MOA(SDADSS)• Partial Agonist• Sedation• 효능 : Efficacy & Effectiveness• 안전성 : 대사장애 , 체중증가 , 고프로락틴 유발 위험 없다 . • 다양한 적응증

16

Aripiprazole and Dopamine Partial Ag-onism

• Aripiprazole is a high-affinity D2 partial agonist– Functional antagonist under conditions of dopamine hy-

peractivity in limbic cortex (i.e., helps in control of posi-tive

symptoms)– Functional agonist in conditions of dopamine hypoactivity

in prefrontal cortex and basal ganglia (ie, control of nega-tive symptoms, cognitive improvement, minimal motor ef-fects)

Burris et al. J Pharmacol Exp Ther. 2002;302:381.

Dopamine system stabilizer

Aripiprazole Pharmacology related to Serotonin Rc

• Abilify also has a partial agonism effect at 5-HT1A receptors. 5-HT1A receptors is associated with im-provements in anxiety, depression, cognitive and negative symptoms, and decreased risk of EPS. 5-HT1A 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.

17

Aripiprazole Activity at Receptors Associated To Its Side Effects• Moderate-low affinity at 1 and H1;

no affinity for muscarinic receptor sub-types

• Potential clinical impact– Low propensity for orthostatic hy-

potension(1-adrenergic receptors)

– Low liability for weight gain and som-nolence(H1 histamine receptors)

– Low potential for cognitive impair-ment (muscarinic cholinergic receptors)

Data on file. 18

19

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 ?

REAL WORLD CONSIDERATION OF ACUTE MANAGEMENT

Issues of Abilify Start-ing• 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 con-comitant therapy

– Activation issue associated with dose in acute phase- generally, activation occurs at a low dose- to manage activation, inc dose or use BZ

21

Aripiprazole, Ziprasidone, and Que-tiapine 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)

26

The efficacy of aripiprazole in the treat-ment 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, An-drei Pikalov c,Richard Whitehead c, David T. Crandall ba The Zucker Hillside Hospital, New York, NY, USAb Bristol-Myers Squibb, Plainsboro, NJ, USA

Schizophrenia Res. 2008;105:208-215

27

Changes in PANSS total score & Subscale scores

28

PANSS Positive Items

29

PANSS Negative Items

30

PANSS General Psychopathology Items

Olanzapine versus Aripiprazole for the treatment of Agitation in Acutely

ill patients with Schizophrenia . J Clin Psychopharmacol 2008;28:601-607.

31

Study Design• 5-day, randomized, double-blind

trial• Ho : Owing to its pure antagonist

activity, olanzapine would be su-perior to aripiprazole in reducing agitation and positive symptoms early in the treatment of acutely ill patients.

32

-10

-8

-6

-4

-2

Visit 2 Visit 3 Visit 4 Visit 5

OlanzapineAripiprazole

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 baseline score. Kinon, 2008

PANSS-EC Score Change

34

Metabolic Parameters

Glucose (mg/dL) Triglycerides (mg/dL)Prolactin (μg/L)

0

5

10

15

20

25

30

35

-40

-30

-20

-10

0

10

20

0

20

40

60

80p=0.030 p<0.001

p<0.001

Olanzapine Aripiprazole

Kinon, 2008

Akathisia concern with Abilify• About 10~20% of patients(3~5%)• Generally mild to moderate in inten-

sity• Treat as you would with other an-

tipsychotics– Consider dose reduction– Treat with beta blockers

• Not generally associated with discon-tinuation

35

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 accompa-nied by increased nervous and restless movement• Subtypes : 1) withdrawal 2) acute 3) tardive akathisia• BARS(Barnes Akathisia Rating Scale)

38

Akathisia, Agitation, Activation, and Aggravation

Activation

Yes

Yes(?)

Improve

No Re-sponsePsycho-motor

Syntonic

Akathisia Agitation

Concentra-tion NO Yes

Control No Yes

APs Worsen Improve

An-tiparkin-son Drug

Imp No re-sponse

Symptoms Motor psychosis

Ego-tonic-ity Dystonic Dystonic

Aggravation

No

No

Improve

No response

psychomotor

Syn- or dys-tonic

Summary - Results• Akathisia with Aripiprazole - occurred early in treatment - mild to moderate in severity - led to few study discontinuations - did not compromise therapeutic effi-cacy

Proposed strategies for successful clinical management with Aripipra-

zole

Mago R. Expert Opinion Phar-macother 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

46

Dosing Strategies(Expert Opinion)

Rapid/High-dose Slow/Low-dose

Patients younger olderhealthy medical co-

morbidmotivated for tx ambivalent

Illness acute exacerbated stable sxagitated calm

Treatment inpatient outpatienttolerating Aps drug naïve, in-

tolerOthers good support limited support

Clinical Factors

47

Rapid/High-dose Slow/Low-dose

Starting D 20mg 5mgTarget 30mg 10mgSpeed immediate 1 week

observe safety/se 2nd dayincrease or decrease

Taper period 4-8 weeks(clo, olan 12weeks) begin tapering

when target dose reached

Worsening inc dose or add on incr dose

Proposed Initiation/Dosing Strategies

48

• 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

Factors Modifying Dosing Strategies

49

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 bed-

time dose reduce the dose Insomnia ; morning dose with food & add hyp-

notics Nausea/vomiting ; food, reduce dose, bed time,

dividing dose EPS ; Worsening symptoms

Management of adverse events with Aripiprazole

50

Summary : Abilify – Acute Tx.• Behavior control

- Separate sedation issue from acute effi-cacy

- 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 51

52

Conclusions(1)• Clinically relevant differences exist

among atypicals in their propensity to cause AE- Sedation, Prolactin elevation, Weight gain & other metabolic ef -fects

Sedation, Metabolic & Sexual is-sues : QoL, Medication adherence Improved Outcome

Aripiprazole : effective as other SDA, but minimal adverse effects.

53

Conclusions(2) Paradigm Shift

- DA Antagonist Partial DA Ago-nist- Sedating Non-sedating Agents

Enhancing Physical Health- Metabolic Syndrome & - Sexual Dysfunction

Balancing Mental & Physical Health Imp QoL & Promoting Community Reentry

54

多 謝 !!

Thank You for Your Time and Attention !!