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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

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Journal Club Psychiatry rotation

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  1. 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

  3. Clozapine • Weak antagonist at: • 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

  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

  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

  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

  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 collected @ 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 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

  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

  15. Scales Used to Test Efficacy (Neurocognitive) WCST: Wisconsin Card Sorting System Verbal Fluency Test Stroop Colour-word Test

  16. Demographic & Clinical Characteristics of the Clozapine Groups

  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

  19. Results

  20. 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

  21. 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%)

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

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

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