Predicting relapse in schizophrenia: Is BDNF a plausible biological marker?
Introduction
Schizophrenia is, by any estimate, a disorder of major public health significance. Although treatment options for this disabling condition have increased (and improved) over time, it is sobering that schizophrenia is still characterized by persistent functional impairment and recurrent psychotic relapses for most/many patients. Wyatt (1991) proposed that relapse in schizophrenia was a biologically toxic event, leading successively to deteriorations in course of illness and overall functioning. Complementarily, Loebel et al. (1992) showed that each successive relapse among first episode schizophrenia patients was more prolonged than the prior relapse. A longitudinal MRI study of patients with schizophrenia found that relapse was associated with progressive loss of cortical tissue and overall brain volume (Andreasen et al., 2013). Ample and compelling evidence, largely from antipsychotic withdrawal and maintenance studies with a placebo-controlled condition (Gilbert et al., 1995, Kane, 1996, Schooler et al., 1997) shows that patients with schizophrenia have an inordinately high risk of relapse over time if they are not receiving treatment with antipsychotic medications. More recent evidence suggests that second-generation antipsychotic (SGA) medications reduce the risk of relapse when compared to first generation antipsychotics (FGAs) (Leucht et al., 2003). Thus, it is plausible that relapse is more than an expression of worsening psychopathology but may represent some fundamental pathobiological event and/or follow some discrete neurobiological trajectory. However, the underlying neurobiological mechanisms that drive these effects are not clear. We have previously proposed that brain derived neurotrophic factor (BDNF) might be a biological marker underlying a cascade of events in relapse in schizophrenia (Pillai and Buckley, 2012).
There is intense interest in the discovery and application of biomarkers to major mental illnesses (Arnow et al., 2015, Ivleva et al., 2016, Weickert et al., 2013). BDNF plays a critical role in neurodevelopment and neuronal and synaptic plasticity (Lu et al., 2014). A number of preclinical, clinical, as well as imaging studies indicate a potential role of BDNF in the pathophysiology of schizophrenia (Ahmed et al., 2015, Buckley et al., 2011, Harrisberger et al., 2015). For example, post-mortem studies show that schizophrenia patients have lower BDNF mRNA levels in the prefrontal cortex and hippocampus (Reinhart et al., 2015, Thompson Ray et al., 2011, Weickert et al., 2003). Concentrations of BDNF in cord blood from infants exposed to obstetric complications who later developed schizophrenia were lower than in cord blood from exposed infants who did not develop the disorder (Cannon et al., 2008). Serum and plasma BDNF levels in adult schizophrenia patients are generally reduced compared with healthy subjects, including never-medicated, first-episode patients (Buckley et al., 2007, Pillai, 2008, Pandya et al., 2013). In animal experiments, the acquisition and maintenance of spatial memory are impaired when BDNF signaling is decreased (Mizuno et al., 2000a, Mizuno et al., 2000b, Linnarsson et al., 1997); however, brain BDNF is increased when rodents perform a spatial learning task (Mizuno et al., 2000a, Mizuno et al., 2000b) or are housed in cognitively stimulating environments (Ickes et al., 2000). Indeed, Vinogradov et al. (2009) found that schizophrenia subjects who participated in 10 weeks of neuroplasticity-based computerized cognitive training showed a significant increase in serum BDNF compared with carefully matched control subjects. Together, these studies indicate that peripheral BDNF levels may serve as a biomarker for clinical outcomes in schizophrenia subjects.
The PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables eValuating Efficacy) study was a clinical trial evaluating relapse and clinical outcomes over 30 months in patients who were randomly assigned to receive the long-acting SGA, risperidone microspheres (LAI-R), or oral SGAs. Serial plasma samples collected from the patients enrolled in PROACTIVE were examined to test the hypothesis that a decrease in plasma BDNF levels could predict relapse in schizophrenia. Also, the relationship between plasma BDNF and hospitalization or exacerbation was examined at baseline and follow up visits. Based upon the prevailing findings, albeit from smaller and often cross sectional studies of BDNF, this study was funded by the National Institute of Mental Health (clinicaltrials.gov NCT00330863) as a translational component to the already funded PROACTIVE study to allow a rigorous and longitudinal evaluation of BDNF and relapse in schizophrenia.
Section snippets
Study design and subjects
The study is described in detail in an earlier publication (Buckley et al., 2015) and was approved by Institutional Review Boards at all sites and at the coordinating center. In brief, 305 patients with a DSM IV-TR diagnosis of schizophrenia or schizoaffective disorder were enrolled at eight U.S. academic centers and randomly assigned to receive either LAI-R or physician's choice of oral SGA medication. Following randomization, clinical teams on-site were not blinded to treatment assignment;
Results
We collected a total of 2315 plasma samples from 221 of the 305 study participants. The number of BDNF values (corresponding to the number of visits at which a blood sample was collected for BDNF) obtained per subject ranged from 1 to 23 (median = 11) in the total sample; the numbers were similar in the oral (range 1 to 23, median = 10) and LAI-R (range 1 to 22, median = 12) treatment groups. Table 2 shows the demographic details of the study subjects who had baseline BDNF values.
Discussion
There is intense interest in BDNF in neuroscience and applicability of BDNF measurements as a potential biomarker for mood disorders and schizophrenia in particular. Significant differences in plasma BDNF levels have been found between schizophrenia and control subjects (Buckley et al., 2011). That said, it remains uncertain whether BDNF reflects the underlying illness, trait, or state changes in symptoms of schizophrenia. Moreover, studies on the relationship between antipsychotic treatment
Funding body agreements and policies
The study was supported by funding from National Institute of Health (NIH) (Grant No. U01MH070011-S1)/National Institute of Mental Health (NIMH) to Dr. Buckley (Grant No. U01MH070011).
Contributors
Buckley and Schooler designed the study. Goff, Kopelowicz, Lauriello, Manschreck, Mendelowitz, Miller, Severe, Wilson, Ames, Bustillo and Kane contributed to the subject recruitment and sample collection. Pillai and Peter performed analyses. Looney undertook the statistical analysis. Pillai and Buckley wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors declare that they have no financial interests or potential conflicts of interest related directly or indirectly to this work.
Acknowledgements
We are thankful to Mr. Ammar Kutiyanawalla for his help with BDNF analysis.
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