Effect of Aripiprazole Augmentation of
Clozapine in Schizophrenia: A Doubleblind, Placebo-controlled Study
Journal Club
Psychiatry rotation
Background

15-20% of patients have poor outcome,
treatment resistant

30-50% of treatment resistant patients only
partially responsive to clozapine

Lack of evidence on efficacy & tolerability of
combination treatment with clozapine

Case reports, open-label studies & case series on
clozapine + aripiprazole: promising therapeutic
strategy in residual & treatment-resistant
patients
Clozapine

Weak antagonist at:



D1, D2, D3, and D5
Antagonist at D4: High affinity
Antagonist at 5-HT2A, alphaadrenergic, H1& cholinergic
receptors
Aripiprazole



2nd generation APs: High 5HT2:D2 affinity ratio, lower
affinity for D2
Aripiprazole: Low 5HT2: D2 affinity ratio, higher affinity for
D2
Partial agonist at pre & post synaptic D2 receptors
hypothesized to exert:


Functional antagonist in a hyperdopaminergic
environment
Functional agonist in a hypodopaminergic environment
Aripiprazole




Partial agonist: 5-HT1A
Antagonist at 5-HT2A receptors in mesocortical tract
 postulated to ↑ dopamine release and ↓ negative symptoms
Comparable efficacy to other antipsychotics for +ve
symptoms.
May be beneficial for cognitive, negative & mood
symptoms
Receptor Binding Profile and Possible
Clinical Implications
Receptor
Clozapine
Aripiprazole
Possible Clinical Implications
D2 (Partial agonist)
-
++++
improvement in +ve & -ve symptoms
5-HT1A (Partial
agonist)
-
++++
improvement in -ve & cognitive
symptoms
5-HT2A
(Antagonist )
+++
++++
↓ risk for EPS, improvement in –ve
symptoms
α1-adrenergic
+++
+
Postural hypotension, dizziness,
reflex tachycardia
Histamine (H1)
+++
+
Sedation, increased appetite,
weight gain, hypotension
Cholinergic
Muscarinic (M1)
+++
-
Anticholingeric SEs
Pharmacokinetics

F = 87%

Mean T1/2 = 75 hrs

Mean Tmax = 3.0 hrs

Time to steady state ~ 14 days


Dose proportional Cmax & AUC b/w 5 mg and 30 mg
daily
No dose adjustment for renal or hepatic insufficiency
Study Design

Patients: Treatment resistant
schizophrenic patients

Intervention: Aripiprazole

Comparison: Placebo

Outcome: Clinical symptomatology &
executive cognitive functioning
Study Design

Randomized, double-blind, placebo-controlled

Until Week 12: 10 mg/day

After Week 12: 15 mg/ day

5 mg/day of lorazepam allowed for insomnia
or agitation
Study Design

10 visits:




Initial screening (week 1)
Randomization (week 0)
8 further visits at wks 2,4,8,12,16,20 &
24
Data for clinical & neurocognitive
assessments collected @ wks 0,12 and
24
Inclusion Criteria



Met DSM-IV criteria for schizophrenia
Positive & negative symptoms despite an
adequate trial of clozapine
Brief Psychiatric Rating Scale: >25
partial-responders or non-responders
Exclusion Criteria







Any major psychiatric disorder
Significant concurrent medical illnesses
Organic brain disorder
Hx of substance & alcohol abuse
Mental retardation
Pregnant or lactating women
No Anti-Depressant or Anti-Convulsant
for 2 months before study
Patient Characteristics
N = 40
M = 23, F = 17
Age: 25-38 years

On clozapine monotherapy at highest tolerable range
(200-450 mg/day) for at least 1 year

Dose stable for at least 1 month

Dose unchanged throughout the study
Scales Used to Test Efficacy
(Psychopathological)




BPRS: Brief Psychiatric Rating Scale
SANS: Scale for the Assessment of
Negative Symptoms
SAPS: Scale for the Assessment of
Positive Symptoms
CDSS: Calgary Depression Scale for
Schizophrenia
Scales Used to Test Efficacy
(Neurocognitive)

WCST: Wisconsin Card Sorting System

Verbal Fluency Test

Stroop Colour-word Test
Demographic & Clinical Characteristics of
the Clozapine Groups
31 completed study Aripiprazole group
Placebo group
Patients entered
20
20
Patients evaluable
14
17
Sex (M/F)
8/6
9/8
Age (years), mean
+SD
31.9 + 3.9
30.7 +5.3
Clozapine dose
310.7 + 73.1
(mg/day) mean + SD
341.2 + 77.5
Dropouts
3 dropouts (noncompliance, changed
mind)
6 dropouts
(concurrent illness,
non-compliance with
visits)
Lorazepam Use for Insomnia or Agitation

Aripiprazole group:



Placebo group:



Patient 1 = 2.5 mg/day
Patient 2 = 5 mg/day
Patient 1,2 = 2.5 mg/day
Patient 3 = 5 mg/day
Small N, no statistical analyses performed
Results
Results
Results

Positive symptoms: Aripiprazole > Placebo



SAPS total scores
Domains delusions & bizarre behaviour
Negative symptoms: Aripiprazole > Placebo



Single domain of alogia
Lower reduction than expected
Mild negative symptoms

↑ in overall psychopathological state: Changes in BPRS

Affective symptomatology: No changes in CDSS
Results




Positive & general psychopathological
symptomatology: Beneficial effect
Executive cognitive functions: No significant
effects
Safety: generally well-tolerated
Most common SEs: restlessness (N=5,
35.7%), insomnia (N=3, 21.4%), nausea (N
=1, 7.1%)
Results from other studies

Double-blind RCT (Chang et al.): No advantage for
total symptom severity

Secondary analyses: Significant ↑ in negative symptoms
and overall clinical state (BPRS scores)

Limited evidence on cognition

Open label RCT, N= 169



↑ in general cognitive functioning
Significant ↑ in verbal learning
Case report: ↑ in verbal memory, reaction time,
quality/attention
Investigators’ Conclusion



Combination well-tolerated
May be of benefit for patients partially
responsive to clozapine monotherapy
Further double-blind, placebo controlled
trials in a larger number of patients
required
Critical Appraisal Skills
Programme (CASP) RCT Checklist





Did the study ask a clearly focused question? Yes
Was this a randomized controlled trial (RCT) and was it
appropriately so? Yes
Were participants appropriately allocated to
intervention and control groups? Yes
Were participants, staff and study personnel ‘blind’ to
participants’ study group? Yes
Were all of the participants who entered the trial
accounted for at its conclusion? Yes
Critical Appraisal Skills Programme
(CASP) RCT Checklist

Were the participants in all groups followed up and data
collected in the same way? Yes

Did the study have enough participants to minimize the play of
chance? No

How are the results presented and what is the main result?
Augmentation beneficial for on positive & general
psychopathological symptomatology
 No significant effects regarding executive cognitive
functions


How precise are these results?

Were all important outcomes considered so the results can be
applied? Concurrent medical conditions, medications
Limitations


Small sample size
Relatively low dose of aripiprazole
 May have prevented enhanced therapeutic effects
 No discussion regarding biphasic titration

Practice effects

No information on clozapine levels

Patient status: smoker vs. non-smoker
Limitations


SEs data:
 No data regarding metabolic SEs
 Clinical interview
 Non-specific questioning
 No formal psychometric measure of EPS
Inter-rater reliability not established
by formal training
Implications to Practice



Polypharmacy not the best option in
terms of antipsychotics
Trial in patients with partial
response to clozapine
More RCTs required