Mechanisms of Illness Progression in the Recurrent Affective Disorders

Abstract

Along with genetic vulnerability, multiple environmental factors convey liability to illness progression, including: (1) distal and proximal stressors; (2) recurrence of episodes; and (3) comorbid cocaine abuse. Recurrence of each of these can increase responsivity (sensitize) to themselves and cross-sensitize to the two other factors and drive illness progression as seen clinically in increases in cycle acceleration, severity or duration of episodes, treatment refractoriness, disability, cognitive dysfunction, and premature death. Some mechanisms appear common to all three types of sensitization, such as decreases of brain-derived neuroprotective factor (BDNF) in hippocampus and blood, as well as increases in BDNF in the nucleus accumbens, suggesting the possibility that single treatments could ameliorate several of these factors at once. A potential example is N-acetylcysteine (NAC), which decreases bipolar affective illness severity (Berk et al. Biol Psychiatry 64:468–475, 2008) and cocaine reinstatement and craving (Baker et al. Ann N Y Acad Sci 1003:349–351, 2003; LaRowe et al. Am J Addict 15:105–110, 2006). Mechanisms of illness progression also involve epigenetic changes and add further rationale to the existing empirical clinical evidence of the importance of early recognition, treatment, and prevention of affective episodes. Adequate treatment could prevent or ameliorate both the increases in pathological factors and erosion of adaptive factors that propel illness exacerbation and treatment resistance. This view of the sensitization and cross-sensitization among stressors, episodes, and abused substances should lead to a fundamental re-conceptualization of the recurrent affective disorders not as benign, isolated episodes of “mental” illness, but as severe, potentially progressive and lethal medical disorders of brain and body that deserve careful life-long monitoring and treatment.

Circuits Regulating Pleasure and Happiness—Mechanisms of Depression

“…This theory holds that, analogous to the relationship between kindling and convulsions, some stressors may produce increasing effects over time, which culminate in a full-blown affective episode (Post, 2007, 2010). For example, the more often unipolar or bipolar episodes occur, the more vulnerable one is to recurrences and the development of cognitive dysfunction (Post et al, 2012).…”

The International College of Neuropsychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 1: Background and Methods of the Development of Guidelines

“…Up to n, 5 major staging models have been proposed for BD (Berk et al, 2007a, 2007b; Kapczinski et al, 2009; Post, 2010; Post et al, 2012; Cosci and Fava, 2013; Frank et al, 2014). Although there is some support for the proposed staging models, the research base is thin, the heterogeneity of the data is significant, and the studies include small sample sizes.…”

Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression

“…Cross-sensitization between different kinds of stressors is possible [11]. For example, previous studies in rats showed that an inflammatory challenge potentiates a later response to psychosocial stress [12,13].…”