1. Journal Club Psychiatry rotation
Effect of Aripiprazole Augmentation of Clozapine in Schizophrenia: A Double-blind, Placebo-controlled Study
Journal Club
Psychiatry rotation

2. 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: treatment of choice for non-responder schizophrenic patients
Few extrapyramidal adverse events and a beneficial effect in terms of mental state and suicide mortality
Adverse events: sedation, postural hypotension, tachycardia, seizures, hypersalivation, agranulocytosis

3. Clozapine Weak antagonist at: Antagonist at D4: High affinity
D1, D2, D3, and D5
Antagonist at D4: High affinity
Antagonist at 5-HT2A, alpha-adrenergic, H1& cholinergic receptors

4. 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
Extensive metabolization in the liver

5. 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 ,

6. Receptor Binding Profile and Possible Clinical Implications
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

7. 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
Dose proportional Cmax and AUC b/w 5 mg and 30 mg daily

8. Study Design Patients: Treatment resistant schizophrenic patients
Intervention: Aripiprazole
Comparison: Placebo
Outcome: Clinical symptomatology & executive cognitive functioning

9. 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
Psychiatry unit of university hospital of Messina, Italy
Biphasic titration to test if efficacy is dependent on dose
15 mg/day established according to previous studies

10. 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 wks 0,12 and 24

11. 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

12. 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

13. Patient Characteristics
M = 23, F = 17
Age: years
On clozapine monotherapy at highest tolerable range ( mg/day) for at least 1 year
Dose stable for at least 1 month
Dose unchanged throughout the study
Lorazepam use
Make a chart

14. 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
The Brief Psychiatric Rating Scale (BPRS) is rating scale which a clinician or researcher may use to measure psychiatric symptoms such as depression, anxiety, hallucinations and unusual behaviour.[1] Each symptom is rated 1-7 and depending on the version between a total of symptoms are scored.

15. Scales Used to Test Efficacy (Neurocognitive)
WCST: Wisconsin Card Sorting System
Verbal Fluency Test
Stroop Colour-word Test
Test were selected for the inclusion of functions frequently attributed to the frontal lobes and widely used in the study of cognition in schizophrenia

16. Demographic & Clinical Characteristics of the Clozapine Groups
31 completed study
Aripiprazole group
Placebo group
Patients entered 20
Patients evaluable 14 17
Sex (M/F)
8/6
9/8
Age (years), mean +SD
Clozapine dose (mg/day) mean + SD
Dropouts
6 dropouts (concurrent illness, non-compliance with visits)
3 dropouts (non-compliance, changed mind) 16

17. 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

18. Results Clinical symptoms @ baseline
No significant differences b/w A and P on SANS, SAPS, BPRS, CDSS
Wk 12: SD on SAPS domain “Thought disorders” and total scores
Wk 24: SD on SAPS domain “Bizarre behavior” and total scores
Wk 24: SANS domain “Alogia”
Within group
SAPS domain “thought disorders” and total score and overall clinical symptomatology (BPRS)

19. Results
Cognitive performances: no SD except for Semantic fluency that worsened from wk 12 to wk 24.

20. Results
Clinical symptoms at baseline: no significant differences b/w A & P on SANS, SAPS, BPRS and CDSS scores
Wk 12: significant differences on SAPS domain “Thought disorders” and total score
Endpoint: Significant differences b/w groups
R non-inferior to enoxaparin

21. 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

22. 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%)
Compare with SEs listed in monographs
Type and percentage
>10%:
Central nervous system: Headache (27%; injection 12%), agitation (19%), insomnia (18%), anxiety (17%), EPS (dose related; 5% to 16%; children 6% to 26%), akathisia (dose related; 8% to 13%; injection 2%), sedation (dose related; 5% to 11%; children 8% to 24%; injection 3% to 9%)
Gastrointestinal: Weight gain (8% to 30%; highest frequency in patients with BMI <23), nausea (15%; injection 9%), constipation (11%), vomiting (11%; children 9% to 14%; injection 3%), dyspepsia (9%)
Central nervous system: Dizziness (10%; injection 8%), pyrexia (children 5% to 9%), restlessness (5% to 6%), fatigue (dose related; 6%; children 8% to 17%; injection 2%), lethargy (children 2% to 5%), lightheadedness (4%), pain (3%), dystonia (children 1%), hypersomnia (1%), irritability (children 1%), coordination impaired, suicidal ideation

23. 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

24. 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

25. 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

26. 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

27. 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
Same person administered psychopathological & cognitive tests. Conducted clinical interviews
& were well versed with use of scales

28. 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

29. Implications to Practice
Polypharmacy not the best option in terms of antipsychotics
Trial in patients with partial response to clozapine
More RCTs required