Journal Club Psychiatry rotation 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: 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

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

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

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

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 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

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 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 Lorazepam use Make a chart

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 18-24 symptoms are scored.

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

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 31.9 + 3.9 30.7 +5.3 Clozapine dose (mg/day) mean + SD 310.7 + 73.1 341.2 + 77.5 Dropouts 6 dropouts (concurrent illness, non-compliance with visits) 3 dropouts (non-compliance, changed mind) 16

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 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)

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

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

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%) 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

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

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