Plasma peptidases as prognostic biomarkers in patients with first-episode psychosis
Introduction
Schizophrenia is a severely debilitating mental illness that, worldwide, is estimated to affect 1% of the population and is among the top 10 causes of disability-adjusted life years, together with depression and bipolar disorder (Rossler et al., 2005). It is clinically complex and, though it is believed to have a neurobiological basis, it currently still diagnosed on the basis of symptom profiles, using standardized criteria (of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-V] or the World Health Organization׳s International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]). Symptoms are heterogeneous, including cognitive deficits, in working memory, attention and cognitive flexibility, as well as so-called “positive” symptoms, such as hallucinations and delusions and “negative” symptoms, such as avolition and reduced affect (Winchester et al., 2014). These symptoms overlapping with other mental illnesses, in particular bipolar disorder, the appropriateness of the current classification and diagnosis of neuropsychiatric disorders continue to be debated (Craddock and Owen, 2010, Kapur et al., 2012).
Research into cognitive performance of patients in the early stages of schizophrenia is useful for several reasons. In particular, though prodromal symptoms and even very short periods of psychotic symptoms may be associated with cognitive changes, assessing performance at this stage is likely to shed new light on the disorder, most research so far having been done in patients at much later stages. It may be possible to identify cognitive deficits related to neural dysfunction underlying the symptoms, before these are masked by effects of the illness and/or treatment. Indeed, data from the early stages may demonstrate whether some cognitive changes observed later in the course of the disease are attributable to long-term drug treatments. Notably, some studies on first-episode psychosis have grouped patients with a diagnosis of schizophrenia together with those with other psychoses. Since such early-stage diagnoses may change, this inclusive approach has the advantage of not excluding potential schizophrenia cases (Aas et al., 2014).
The aminopeptidase family of proteases is involved in the proteolytic processing of precursor proteins to produce biologically active neuropeptides and hormones (Deng et al., 2013). These include dipeptidyl-peptidase (DPP-IV) (Boonacker and Van Noorden, 2003), prolyl-oligopeptidase (PEP) (Maes et al., 1995) and aminopeptidase N (APN) and aminopeptidase B (APB). In recent years, considerable evidence has emerged for the presence of APN in the brain. The APN receptor has been detected in regions of the mouse hypothalamus, brainstem and cortex (Thundyil et al., 2012). Elevated blood levels of APN have been reported in several brain disorders including bipolar disorder (Breen et al., 2004, Elmslie et al., 2009), mild cognitive impairment and Alzheimer׳s disease (Une et al., 2011), and schizophrenia (Beumer et al., 2012). DPP-IV selectively removes amino-terminal dipeptides from precursor proteins containing proline or alanine in the second position (Lambeir et al., 2003) and is widely distributed (Mentlein, 1999). It is present as both membrane-bound and circulating forms with indistinguishable protease activity (Drucker, 2003). It is also involved in the processing of bioactive peptides that are involved in regulation of mood and behavior (Maes et al., 1998). Hence, it is relevant to explore the involvement of aminopeptidase activity in synaptic neuropeptide degradation and control to elucidate the neurochemical mechanisms that are on the basis of mental health and neurological diseases, as is the case for aminopeptidase control of opioid peptides (Hui, 2007).
The aminopeptidases have been linked to the pathophysiology of various diseases including neuropsychiatric disorders and metabolic conditions such as type II diabetes mellitus (Drucker, 2003). Although first-episode psychosis is a severe mental disease primarily affecting the brain, it is becoming more apparent that the whole body is involved (Hildebrandt et al., 2000, Brandt and Bonelli, 2008). Studies over the last two decades have shown that many patients with first-episode psychosis have inflammatory, hormonal and metabolic abnormalities, similar to those seen in cardiovascular diseases and diabetes (Hildebrandt et al., 2000).
DPP-IV has been proposed as a diagnostic or prognostic marker for various cancers but also for neuropsychiatric disorders. Specifically, previous studies have indicated that changes in aminopeptidase activity may be involved in neuropsychiatric conditions such as first-episode psychosis (Maes et al., 1998). Further, low serum DPP-IV levels have been associated with neuropsychiatric conditions such as psychosis and anorexia nervosa (Hildebrandt et al., 1999). We considered it particularly interesting to explore whether differences in these enzymatic activities could be used as a means of classifying patients with first-episode psychosis compared to controls. To our knowledge, no previous prospective studies have assessed the value of aminopeptidases as biomarkers in this population.
Given all this, the aim of this study was to analyze plasma samples from a large cohort of patients with first-episode psychosis compared with healthy controls in an attempt to characterize changes in the activities of DPP-IV, APN, APB and other aminopeptidases in this disorder.
Section snippets
Methodology
A total of 119 patients (men 78, 65.54%; women 41, 34.45%) with first-episode psychosis (aged between 17–62 years) were included in the study. All of them were inpatients of the Service of Psychiatry, Hospital Universitario de Alava (Basque Health Service/Osakidetza, Vitoria, Spain) admitted between 2009 and 2012 (mean age at initial diagnosis: 30.29±9.94 years). This is a regional hospital that receives referrals of all individuals with acute psychiatric episodes from a geographic area of
Results
The final diagnoses at 12 months, listed in Appendix 1, were not significantly related to patient sex (p=0.923). Data on the activity of the selected plasma aminopeptidases followed a normal distribution both in controls and patients at all stages, justifying the statistical analysis reported below. However, it should be noted that p values close to the threshold for significance were found considering patient levels of APB and PSA at 12 months, as well as in APN and Cys-AP in the time of the
Discussion
Our results indicate that levels of plasma aminopeptidase activity at the onset of a first episode of psychosis could have a role as clinical prognostic indicator. Elevated plasma levels of APN have been reported in several brain disorders including bipolar disorder (Elmslie et al., 2009), mild cognitive impairment and Alzheimer׳s disease (Une et al., 2011), and schizophrenia (Beumer et al., 2012). In line with this, we observed significantly higher APB, APN and DPPIV plasma activity in
Role of funding source
Funding for this study was provided by the Biomedical Research Network on Mental Health (CIBERSAM) and the Carlos III Health Institute of the Spanish Ministry of Health and Innovation, who had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
Gonzalez-Pinto and Echevarria designed the study and wrote the protocol. Gonzalez-Pinto and Martínez-Cengotitabengoa managed the literature searches and analyses. Fernández-Atucha and Martinez-Cengotitabengoa performed the laboratory analysis. Seco and Echevarría undertook the statistical analyses and wrote the first draft of the manuscript. Irazusta and Gil made contributions to the discussion of the manuscript and revised the final version. All authors contributed to and have approved the
Conflicts of interest
None.
Acknowledgments
The authors would like to thank the mental health professionals who helped with this research, as well as Prof. Ismael Barbero for his statistical assistance.
This work was supported by CIBERSAM. Preparation of this report was supported by Health Research Funds from the Spanish Government (FIS: PS09/02002, PI08/90439, PI08/90224, PI081213, PI081536, PI08/0873, CIBER, P91A, P91E EC07/90435, EC07/90666, CD08/00269, and CM08/00213), the European Regional Development Funds (FEDER), and local Grants
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- 1
Dpt. Physiology, Fac. Medicine, University of the Basque Country, Barrio Sarriena, s/n 48940, Leioa – Bizkaia, Spain. Tel.: +34 946 01 3427.
- 2
Dpt. Physiology, Fac. Pharmacy, University of the Basque Country, Paseo de la Universidad 7, 01006 Vitoria, Spain. Tel.: +34 945 013035.
- 3
Dpt. Physiology, Fac. Medicine, University of the Basque Country, Barrio Sarriena, s/n 48940, Leioa – Bizkaia, Spain. Tel.: +34 946 01 2837, +34 946 01 2064.
- 4
Dpt. Physiology, Fac. Medicine, University of the Basque Country, Barrio Sarriena, s/n 48940, Leioa – Bizkaia, Spain. Tel.: +34 946 01 5657, +34 946 01 2182.
- 5
International Mood Disorders Research Centre, Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Hospital Universitario de Alava, Spain; National Distance University (UNED), Spain; c/ Olaguibel, 29, 01004 Vitoria-Gasteiz, Álava, Spain. Tel.: +34 945007769; fax: +34 945007764.
- 6
International Mood Disorders Research Centre, Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Hospital Santiago Apóstol, University of the Basque Country, Vitoria, Spain; c/ Olaguibel, 29, 01004 Vitoria-Gasteiz, Álava, Spain. Tel.: +34 945007769; fax: +34 945007764.
- 7
Visiting Researcher and Professor University of the Basque Country, Spain.