Biomarkers in Psychiatry - A Critique

Abstract

In the past decades, cutting-edge research techniques have facilitated better understanding of the bi-directional ‘vectors of influence’ that link the genes, brain and social behavior. This, in turn, has led to remarkable progress in biological research principles, paradigms and processes, having rendered critical insights on the pathogenesis of various psychiatric disorders. For instance, neuroimaging has revolutionized the research on understanding the biological underpinnings of several psychiatric disorders [1]. Coupled with the immense expansions on the computational techniques and resources to handle ‘big-data’, the neuroimaging procedures have facilitated non-radioactive, non-invasive research to examine the in vivo brain aberrations in patients with psychiatric manifestations [2]. These techniques attempt to profile the ‘panorama’ of brain dysfunction involving structural, neurohemodynamic, neurochemical as well connectivity aspects. One is hopeful that these significant advances in neuroimaging techniques will pave the way for insights about the disruption of neural networks in neuropsychiatric disorders (pathoconnectomics) [3]. In tandem with vast advances in neuroimaging research, the progress in molecular biology involving genomics, proteomics and several other related fields have been astonishing. Noteworthy among such advances is the feasibility of utilizing ‘stem cell models’ to characterize the complex pathogenetic interactions that underlie the genesis of complex psychiatric disorders [4]. These exciting advances have generated immense hope and novel avenues for identifying biomarkers for psychiatric disorders. A biomarker is defined as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes or biological responses to a therapeutic intervention’ (Biomarkers Definition Working Group [5]); a biomarker can involve a gene or a set of genes, proteins/other biomolecules, morphological characteristic. In terms of application, biomarkers can be used for diagnosis or prognosis [6]. Thus, biomarkers are critically needed for diagnosis, predicting treatment response and follow-up outcomes of medical ailments [7]. Although, ‘concerted’ research efforts in the ‘decade of the brain’ and the years that followed have unravelled critical insights on the pathogenesis of psychiatric disorders, clinically translatable biomarkers in psychiatry are yet to be identified. For instance, a recent publication which performed a systematic and qualitative review of clinically meaningful biomarker for psychosis by examining 3,200+ studies could identify just one study that passed the author's threshold of clinical applicability [8]. A ‘snap-shot’ review on the status of biomarkers in certain major psychiatric disorders reiterates this lag. For instance, in Alzheimer's disease, current research studies suggest that about 8 biochemical measurements (amyloid proteins and their A-beta precursors or tau proteins) or brain imaging procedures (advanced structural/functional/neurochemical imaging techniques) are considered as potential biomarkers [9]. However, there are none that might qualify for the ‘rigorous’ definition of biomarker [8]. Recent findings needing further confirmation suggest that reductions in plasma phospholipid levels might be useful in accurate prediction of the development of Alzheimer's dementia within 2 years [9]. The status of biomarkers is almost the same in another important psychiatric disorder of significant public health implication - autism. In autism, while there are promising leads for potential biomarkers that involve parameters of mitochondrial function, oxidative stress, immune system or certain gene clusters, a clinically translatable biomarker is yet to be identified [10]. All these reiterate the fact that the current status of biomarkers in psychiatry has significantly lagged behind in comparison with other medical specialties. In most of the existing studies on biological abnormalities of psychiatric disorders, patients are distinguishable as a group from healthy controls; however, these differential biological correlates have not been transformed into clinically useful biomarkers. The following are some of the critical reasons for this lacuna [7,11]: (a) current classificatory and diagnostic systems in psychiatry are primarily symptom based, (b) methodological limits of the existing studies on biological abnormalities in psychiatry, (c) lack of valid ‘in-vitro’ models for psychiatric disorders and (d) issues related to conceptualizations of pathogenetic paradigms for psychiatric disorders.