Dissecting the Heterogeneity of Treatment Response in First-Episode Schizophrenia

The Mental Health Centers for Intervention Development and Applied Research (CIDAR) program prioritized research to provide an evidence base for biomarker development. At the Zucker Hillside Hospital (ZHH), our CIDAR grant supported research on a comprehensive investigation of treatment response and outcome in first episode schizophrenia. Results provide evidence that baseline neuroimaging, neurocognitive, and genetic measures are significantly associated with clinical response to treatment, and that our currently available interventions can effectively treat aspects of psychotic illness, as well as potentially reduce comorbidity associated with illness. Future research may include combining modalities to more robustly predict response and identify treatment targets, as well as to further develop more effective intervention strategies for these devastating and disabling disorders.Key words: schizophrenia, biomarkers, antipsychotic, efficacy, cognitionIn many areas of medicine, heterogeneity of patient outcomes is managed by the availability of multiple therapeutic options, and treatment decisions are guided by clinical biomarkers. Well-known examples in broad clinical use include the HER2 marker for herceptin treatment of breast cancer,¹ and natriuretic peptide levels for diagnosis and prognosis of heart failure.² By contrast, treatment options for patients with schizophrenia are relatively undifferentiated, and clinicians lack objective tools to dissect patient heterogeneity with respect to treatment and prognosis. Development of biomarkers in psychiatry can be critical to both the application of existing treatments and the development of novel treatments.The announcement of the Mental Health Centers for Intervention Development and Applied Research (CIDAR) program in 2005 prioritized research to provide an evidence base for biomarker development. This announcement coincided with an important evolution in research at our institution, the Zucker Hillside Hospital (ZHH). Developments in neuroimaging, neurocognition, and molecular genetics provided the means to broaden our treatment research in first episode schizophrenia to encompass the development of individualized assessment tools to dissect the heterogeneity of treatment response in this important population. The CIDAR program provided the first NIH-funded mechanism to integrate these efforts into a comprehensive investigation of treatment response and outcome in first episode schizophrenia.This theme is focused on the first episode of psychosis, which may be the most critical period in the life of an individual with schizophrenia, and remains the most opportune time for the study of key mechanisms that influence treatment response and outcome of this often chronically disabling disorder. Several factors render the first episode a critical research window: first episode patients are generally young, and therefore within a relatively restricted age range; they have a shorter duration of psychotic symptoms; and less illness-related functional and social impairment related to chronicity of illness. Perhaps most critical is that first episode patients have minimal prior psychopharmacological treatment, reducing medication confounds for research aimed at identifying the neurobiological substrates associated with illness and the prediction of illness course.The ZHH CIDAR (P50MH080173; Dissecting the heterogeneity of treatment response in first episode schizophrenia; PI: Anil K. Malhotra), funded in 2008, integrated therapeutic knowledge and experience with the expertise of investigators utilizing neurocognitive, neuroimaging and molecular genetics approaches to biomarkers development. We focused on the assessment of a cohort of first episode schizophrenia patients participating in a 12-week clinical trial of 2 second generation antipsychotics (SGAs), aripiprazole and risperidone, and a follow-up extension phase of controlled treatment for 1 year. The primary CIDAR assessments were conducted prior to the initiation of treatment and during 12 weeks of double-blind treatment. The CIDAR comprises 3 cores supporting 3 independent projects, with additional NIH and FDA funding to support a supplemental project focused on the reactions of young people with early phase schizophrenia to tobacco smoking warning materials. The major aim of each of the 3 initial projects was to identify predictors of SGA response in this cohort, using neuroimaging, neurocognitive and genetic indices.