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 and risperidone in first-episode psychosis at 3 years.

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 flexible-dose study of two neuroleptics (Aripiprazole and Risperidone) assigned at aleatory ratio 1:1. Rapid titration schedule (5-day), until optimal dose is reached, is 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 are allowed for clinical reasons. No antimuscarinic agents are administered prophylactically. Antidepressants (Sertraline) and mood stabilizers (lithium) are 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 3 years 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.

Inclusion Criteria:

• Patients followed in the First Episode Psychosis Clinical Program (PAFIP III) from January 2015 to December 2020.
• 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.