The concept of staging in bipolar disorder: the role of BDNF and TNF-alpha as biomarkers

Bipolar disorder (BD) is a highly recurrent and disabling illness. Recent evidence suggests a more deleterious course than previously thought. Episode recurrence itself may be a part of illness progression. Stressors and other environmental influences may complicate this, and contribute to a process of accumulating neurobiological alteration. For instance, a greater number of episodes is associated with a declining response to both psychotherapy and pharmacotherapy, and with increasing episode number, the inter-episodic interval typically becomes shorter. Moreover, contrary to previous suggestions that individuals with BD are asymptomatic between episodes and return to baseline levels of social functioning, recent studies have shown a much less satisfactory picture of the long term outcomes (1). These findings raise a possibility of staging BD based on a continuum of severity and incorporation of neurobiological features, both of which will allow a necessary shift in the diagnostic and treatment approach to BD. Indeed, staging models, whereby a disorder is characterised according to severity, extension and features, have achieved wide currency in medicine but are still neglected in psychiatry. These models are useful when the disorder seems to follow a specific course, from an initial presentation which has a higher probability of response and recovery that leads to more chronic and difficult-to-treat stages. The current categorical psychiatric classification tells us little about the prognosis of the disorder in each particular patient. Recent research findings in the field could lead to a more informative classification, with course being a potential specifier, analogous to staging methods used in medical illness, in addition to the current axial classification (2). In this context, the initiative to develop a suitable staging method for BD is receiving increasing attention (3). There are a variety of temporal courses and patterns in BD (4). This trajectory often includes progressive impairment in various areas of functioning, such as cognition, insight and social relationships. These deficits may better indicate illness severity when they persist during remission of mood symptoms. Two staging models have been proposed (1,3), the first emphasising the early stages of the disorder, and by implication, the potential for early intervention, and the second staging model emphasises the inter-episodic period as the most adequate window to perform staging assessment. The stages in the first model are: Stage 0: asymptomatic, at risk, Stage 1, the prodrome, Stage 2, the first episode, Stage 3 recurrence, divided into sub-threshold, threshold and multiple recurrence and Stage 4 is the stage of resistance. The model proposed by Kapczinski includes: Latent Stage: patients at ultra-high risk for developing BD; Stage1: Patients who have the diagnosis of BD and return to their baseline level of functioning when episodes resolve; Stage 2: Mild impairment in functioning due to enduring sub-syndromal BD symptoms or confined to comorbidities; Stage 3: Moderate impairment in functioning due to enduring sub-syndromal BD symptoms which are not resolved with therapy and/or clinically relevant cognitive and functioning; Stage 4: Patients unable to take care of themselves without assistance of family or day-care centres due to unremitting symptoms and/or severe cognitive impairment owing to the disorder. These models need to be validated using a variety of clinical and biological markers. Recent research suggests that in addition to inter-episodic clinical impairment, neurobiological changes are persistent and even progressive in BD. Biochemical markers have been used in medicine for disease characterisation and diagnosis for decades. They are factors that are objectively measured and evaluated as indicators of normal biological processes or pathogenic processes, and can be very valuable in the diagnosis and prognosis of a medical condition for which a specific therapy is intended. BD has been associated with