Effect of Aripiprazole Augmentation of

Clozapine in Schizophrenia: A Double-

blind, 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, alpha-

adrenergic, 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 - ++++ improvement in -ve & cognitive
agonist) symptoms

5-HT2A +++ ++++ ↓ risk for EPS, improvement in –ve

(Antagonist ) symptoms
α1-adrenergic +++ + Postural hypotension, dizziness,
reflex tachycardia

Histamine (H1) +++ + Sedation, increased appetite,

weight gain, hypotension

Cholinergic +++ - Anticholingeric SEs

Muscarinic (M1)
 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 31.9 + 3.9 30.7 +5.3
+SD
Clozapine dose 310.7 + 73.1 341.2 + 77.5
(mg/day) mean + SD
Dropouts 6 dropouts 3 dropouts (non-
(concurrent illness, compliance, changed
non-compliance with mind)
visits)
Lorazepam Use for Insomnia or Agitation

 Aripiprazole group:
 Patient 1 = 2.5 mg/day
 Patient 2 = 5 mg/day

 Placebo group:
 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