Neurocognitive Effectiveness in Treatment of First-episode Non-affective Psychosis: 1-year Follow-up

Study Overview
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Brief Summary
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Cognitive enhancement is a primary goal in treating individuals with schizophrenia. Cognitive deficits are already present at the first break of the illness, seem to remain stable during early phases and noticeably influence daily functioning. Differences among antipsychotics in terms of cognitive effectiveness have turned out to be a topic of increasing research interest. The initially postulated superior neurocognitive effectiveness of second-generation antipsychotics (SGAs) compared to first-generation antipsychotics (FGAs) is currently under debate. Long-term studies would be of great value to evaluate the differential benefits exerted by antipsychotic drugs on cognitive performance. The aim of this study is to investigate the cognitive effects of aripiprazole, quetiapine and ziprasidone in first-episode psychosis at 1 year.

Detailed Description
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Study setting and financial support: data for the present investigation were obtained from an ongoing epidemiological and three-year longitudinal intervention program of first-episode psychosis (PAFIP) conducted at the outpatient clinic and the inpatient unit at the University Hospital Marqués de Valdecilla, Spain. Conforming to international standards for research ethics, this program was approved by the local institutional review board. Patients meeting inclusion criteria and their families provided written informed consent to be included in the PAFIP. The Mental Health Services of Cantabria provided funding for implementing the program. No pharmaceutical company supplied any financial support. Study design: this is a prospective, randomized, flexible-dose, open-label study. Investigators used a simple randomization procedure: a computer-generated randomization list was drawn up by a statistician. Dose ranges were 5-30 mg/day Aripiprazole, 40-160 mg/day Ziprasidone and 100-600 mg/day Quetiapine. Rapid titration schedule (5-day), until optimal dose was reached, was as a rule used unless severe side effects occur. At the treating physician's discretion, the dose and type of antipsychotic medication could be changed based on clinical efficacy and the profile of side effects during the follow-up period. Antimuscarinic medication, Lormetazepam and Clonazepam were permitted for clinical reasons. No antimuscarinic agents were administered prophylactically. Antidepressants (Sertraline) and mood stabilizers (lithium) were permitted if clinically needed. Clinical assessment: the severity scale of the Clinical Global Impression (CGI) scale, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive symptoms (SAPS), the Scale for the Assessment of Negative symptoms (SANS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Young Mania Rating Scale (YMRS) were used to evaluate symptomatology. To assess general adverse event experiences, the Scale of the Udvalg for Kliniske Undersogelser (UKU), the Simpson-Angus Rating Scale (SARS) and the Barnes Akathisia Scale (BAS) were used. The same trained psychiatrist (BC-F) completed all clinical assessments. These clinical data are described at AZQ2005 study. Neuropsychological assessment. Cognitive functioning was assessed in patients at 2 points: baseline and 1 year after the initialization of antipsychotic treatment. The cognitive assessment at baseline was carried out at 12 weeks after recruitment because this time is considered optimal for patients' stabilization. The evaluation required approximately 2 h and was carried out in the same day by the same neuropsychologist (R.A.-A and E.G.-R). The neuropsychological battery comprises 9 cognitive domains: information processing speed, motor dexterity, working memory, verbal learning, visuospatial abilities, delayed memory, attention, executive function and theory of mind.

Official Title
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Neurocognitive Effectiveness in Treatment of First-episode Non-affective Psychosis: a Randomized Comparison of Aripiprazole, Quetiapine and Ziprasidone Over 1 Year

Conditions
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Schizophrenia, Psychotic Disorders

Intervention / Treatment
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* Drug: Aripiprazole
* Drug: Quetiapine
* Drug: Ziprasidone
* Behavioral: Cognitive battery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients followed in the First Episode Psychosis Clinical Program (PAFIP II) from October 2005 to January 2011. Experiencing their first episode of psychosis (First Episode of Psychosis is defined as that psychopathological state in which for the first time and regardless of its duration, the patient has enough severe psychotic symptoms to allow a diagnosis of psychosis, having received no specific psychiatric treatment for him). Living in the catchment area (Cantabria). No prior treatment with antipsychotic medication or, if previously treated, a total life time of adequate antipsychotic treatment of less than 6 weeks. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for brief psychotic disorder, schizophreniform disorder, schizophrenia, or schizoaffective disorder. Exclusion Criteria: Meeting DSM-IV criteria for drug dependence. Meeting DSM-IV criteria for mental retardation. Having a history of neurological disease or head injury with loss of consciousness.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aripiprazole & cognitive battery<br>Aripiprazole 5-30 mg/day. Cognitive battery at baseline and at 1 year. | Drug: Aripiprazole<br>* Oral, dose range 5-30 mg/day, once or twice a day, during study duration<br>* Other names: Abilify;Behavioral: Cognitive battery<br>* Completed in the following standardized sequence: 1-the Rey Auditory Verbal Learning Test (RAVLT); 2-WAIS-III digit symbol subtest; 3-Grooved Pegboard Test; 4-The Zoo Map Test; 5-Tower of London Test (ToL); 6-Rey Complex Figure (RCF); 7-Trail Making Test (TMT); 8-WAIS-III digits forward and backward subtests; 9-WAIS-III letter-number sequencing subtest; 10-WAIS-III vocabulary subtest that was used as measure of premorbid intelligence quotient (IQ); 11-Stroop Test; 12-letter (FAS) and semantic (animal) fluency tests; 14-Eyes Task; 15-Continuous Performance Test (CPT).<br>|
| Active Comparator: Quetiapine & cognitive battery<br>Quetiapine 100-600 mg/day. Cognitive battery at baseline and at 1 year. | Drug: Quetiapine<br>* Oral, dose range 100-600 mg/day, once or twice a day, during study duration<br>* Other names: Seroquel;Behavioral: Cognitive battery<br>* Completed in the following standardized sequence: 1-the Rey Auditory Verbal Learning Test (RAVLT); 2-WAIS-III digit symbol subtest; 3-Grooved Pegboard Test; 4-The Zoo Map Test; 5-Tower of London Test (ToL); 6-Rey Complex Figure (RCF); 7-Trail Making Test (TMT); 8-WAIS-III digits forward and backward subtests; 9-WAIS-III letter-number sequencing subtest; 10-WAIS-III vocabulary subtest that was used as measure of premorbid intelligence quotient (IQ); 11-Stroop Test; 12-letter (FAS) and semantic (animal) fluency tests; 14-Eyes Task; 15-Continuous Performance Test (CPT).<br>|
| Active Comparator: Ziprasidone & cognitive battery<br>Ziprasidone 40-160 mg/day. Cognitive battery at baseline and at 1 year. | Drug: Ziprasidone<br>* Oral, dose range 40-160 mg/day, once or twice a day, during study duration<br>* Other names: Zeldox;Behavioral: Cognitive battery<br>* Completed in the following standardized sequence: 1-the Rey Auditory Verbal Learning Test (RAVLT); 2-WAIS-III digit symbol subtest; 3-Grooved Pegboard Test; 4-The Zoo Map Test; 5-Tower of London Test (ToL); 6-Rey Complex Figure (RCF); 7-Trail Making Test (TMT); 8-WAIS-III digits forward and backward subtests; 9-WAIS-III letter-number sequencing subtest; 10-WAIS-III vocabulary subtest that was used as measure of premorbid intelligence quotient (IQ); 11-Stroop Test; 12-letter (FAS) and semantic (animal) fluency tests; 14-Eyes Task; 15-Continuous Performance Test (CPT).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global cognitive index | In order to calculate a measure of Global Cognitive Functioning (GCF) raw cognitive scores were reversed when appropriate before standardization so they all have the same direction (the higher, the better). According to previous methodology, the GCF was calculated as T-scores, with raw scores of a healthy comparison sample. T scores were converted to deficit scores that reflect presence and severity of cognitive impairment. Deficit scores on all tests were then averaged to create the GCF score. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in information processing speed | Measured by Wechsler Adult Intelligence Scale (WAIS) - III digit symbol subtest (standard total score), Trail Making Test (TMT) trail A and Continuous Performance Test (CPT) reaction time. | 1 year | 
| Change in motor dexterity | Measured by Grooved Pegboard Test (time to complete with dominant hand). | 1 year | 
| Change in working memory | Measured by WAIS - III letter-number sequencing test (standard total score) and WAIS - III digits forward (standard total score). | 1 year | 
| Change in verbal learning | Measured by the Rey Auditory Verbal Learning Test (RAVLT) (trials 1-5). | 1 year | 
| Change in visuospatial abilities | Measured by the Rey Complex Figure (RCF) (copy figure). | 1 year | 
| Change in delayed memory | Measured by RAVLT (list recall and list recognition discrimination subscore) and RCF (delayed recall). | 1 year | 
| Change in attention | Measured by CPT (discrimination subscores). | 1 year | 
| Change in executive function | Measured by TMT trail B, Stroop Test (color-word), the Zoo Map Test (first and second conditions), the Tower of London Test (ToL) (total correct and total moves score) and letter (FAS) and semantic (animal) fluency tests. | 1 year | 
| Change in theory of mind | Measured by Eyes Task (total correct score). | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognition, Psychosis, Antipsychotic Agents, Treatment, Effectiveness, Aripiprazole, Quetiapine, Ziprasidone, Neurocognition