Aripiprazole Augmentation for Clozapine-Treated Patients With Refractory Schizophrenia

A Double-Blind Randomized Placebo Controlled Study of Aripiprazole Augmentation for Clozapine-Treated Patients With Refractory Schizophrenia

The purpose of this study is to determine whether aripiprazole augmentation is safe and effective in the treatment of clozapine-treated patients with refractory schizophrenia.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: placebo; Drug: aripiprazole

Detailed Description

Clozapine is renowned for its efficacy in treating schizophrenia refractory to typical or atypical antipsychotics. Though the effectiveness of clozapine has been established, a considerable number of patients with schizophrenia are partially responsive or unresponsive to clozapine. In addition, long-term use of clozapine is associated with the development of obsessive-compulsive symptoms and metabolic syndrome. In order to overcome these short-comings and to increase efficacy, aripiprazole augmentation was implemented. Quantitative electroencephalogram will be used to monitor the occurrence of abnormal findings and to analyze the changes in electroencephalographic pattern with linear and non-linear methodology.

Comparisons: Design of double-blind randomized placebo controlled study of patients at Refractory Schizophrenia Clinique in Department of Neuropsychiatry at Seoul National University Hospital.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients, 18-65 years of age.
• Patients must have a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).
• Female patients of menarche must be using a medically accepted means of contraception (e.g. oral contraceptives, Depo-Provera, abstinence).
• Each patient must provide written informed consent after full explanation of study protocol, and authorized legal guardian must understand the nature of the study and must also give assent to study participation.
• Patients must have a baseline (day 0) BPRS score of at least 35 or over 2 of 5 SANS global rating item scores of at least 3.
• Patients have been receiving clozapine treatment for more than 1 year and there has been no change in clozapine dosage for more than 3 months.
• Patients must have a history of antipsychotic treatment with at least 2 different kinds prior to clozapine administration.
• Subjects who are fluent in Korean.

Exclusion Criteria:

• DSM-IV substance (except nicotine or caffeine) dependence within the past 1 year.
• Female patients who are either pregnant or lactating.
• Mental retardation (IQ < 70).
• Neurological disorders including epilepsy, stroke, or severe head trauma.
• Clinically significant laboratory abnormalities, on any of the following tests: CBC with differential, electrolytes, BUN, creatinine, hepatic transaminases, urinalysis and EKG.
• Prior history of aripiprazole non-response or intolerance.
• BPRS score of < 35 and over 4 of 5 SANS global rating item scores of < 3.
• Participation in a clinical trial of another investigational drug within 3 months (90 days) prior to study entry.
• Treatment with an injectable depot neuroleptic within less than three dosing interval between the last depot neuroleptic injections and baseline (day 0).
• History of electroconvulsive therapy within the past 3 months.
• Subjects who are not fluent in Korean.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; clozapine plus aripiprazole	Drug: aripiprazole; aripiprazole augmentation of clozapine; Other Names: OPC-14597; abilify
Placebo Comparator: B; clozapine plus placebo	Drug: placebo; placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Brief Psychotic Rating Scale (BPRS): Measure of efficacy will be changes in BPRS total and subscale scores from baseline to 8th week endpoint. Follow-up evaluation will be made every 6th month till 1 year after 8th week end point.	one year
Schedule for Assessment of Negative Symptoms (SANS): Measure of efficacy will be changes in SANS total and subscale scores from baseline to 8th week endpoint. Follow-up evaluation will be made at 6 month and 12 month after 8th week end point.	one year
Serum Prolactin Level	one year
Body Mass Index & Abdominal Circumference	one year
Lipid Panel with LDL Cholesterol	one year
FBS-PP & HbA1c	one year

Secondary Outcome Measures

Outcome Measure	Time Frame
Clinical Global Impression-Severity & Improvement (CGI-S & CGI-I)	one year
Montgomery-Asberg Depression Rating Scale (MADRS)	one year
Yale-Brown Obsessive Compulsive Scale (YBOCS)	one year
Subjective Well-being under Neuroleptics scale (SWN)	one year
Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS)	one year
Udvalg Fur Kliniske Undersogesler (UKU)	one year
Blood Pressure and Pulse Rate	one year
Admission Battery, CBC, & EKG	one year
Serum Clozapine Level	one year
Quantitative Electroencephalogram	one year

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: Korea Otsuka Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Yong Sik Kim, MD, PhD, Seoul National University Hospital

Publications and helpful links

General Publications

• Rocha FL, Hara C. Benefits of combining aripiprazole to clozapine: three case reports. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):1167-9. doi: 10.1016/j.pnpbp.2006.03.024. Epub 2006 May 2.
• Henderson DC, Kunkel L, Nguyen DD, Borba CP, Daley TB, Louie PM, Freudenreich O, Cather C, Evins AE, Goff DC. An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand. 2006 Feb;113(2):142-7. doi: 10.1111/j.1600-0447.2005.00612.x.
• Ziegenbein M, Sieberer M, Calliess IT, Kropp S. Combination of clozapine and aripiprazole: a promising approach in treatment-resistant schizophrenia. Aust N Z J Psychiatry. 2005 Sep;39(9):840-1. doi: 10.1111/j.1440-1614.2005.01688_2.x. No abstract available.
• Chang JS, Ahn YM, Park HJ, Lee KY, Kim SH, Kang UG, Kim YS. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008 May;69(5):720-31. doi: 10.4088/jcp.v69n0505.

Helpful Links

• Click here for detailed information about aripiprazole.

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): December 1, 2006
• Study Completion (Actual): February 1, 2008

Study Registration Dates

• First Submitted: May 17, 2006
• First Submitted That Met QC Criteria: May 17, 2006
• First Posted (Estimate): May 19, 2006

Study Record Updates

• Last Update Posted (Estimate): October 29, 2008
• Last Update Submitted That Met QC Criteria: October 28, 2008
• Last Verified: April 1, 2008

More Information

Terms related to this study

• Keywords: schizophrenia; aripiprazole; clozapine
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Antidepressive Agents; Dopamine Agonists; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Aripiprazole
• Other Study ID Numbers: KYS-2006-05209