Investigating the mechanism(s) underlying switching between states in bipolar disorder

Abstract

Bipolar Disorder (BD) is a unique disorder that transcends domains of function since the same patient can exhibit depression or mania, states with polar opposite mood symptoms. During depression, people feel helplessness, reduced energy, and risk aversion, while with mania behaviors include grandiosity, increased energy, less sleep, and risk preference. The neural mechanism(s) underlying each state are gaining clarity, with catecholaminergic disruption seen during mania, and cholinergic dysfunction during depression. The fact that the same patient cycles/switches between these states is the defining characteristic of BD however. Of greater importance therefore, is the mechanism(s) underlying cycling from one state - and its associated neural changes - to another, considered the ‘holy grail’ of BD research. Herein, we review studies investigating triggers that induce switching to these states. By identifying such triggers, researchers can study neural mechanisms underlying each state and importantly how such mechanistic changes can occur in the same subject. Current animal models of this switch are also discussed, from submissive- and dominant-behaviors to kindling effects. Focus however, is placed on how seasonal changes can induce manic and depressive states in BD sufferers. Importantly, changing photoperiod lengths can induce local switches in neurotransmitter expression in normal animals, from increased catecholaminergic expression during periods of high activity, to increased somatostatin and corticotrophin releasing factor during periods of low activity. Identifying susceptibilities to this switch would enable the development of targeted animal models. From animal models, targeted treatments could be developed and tested that would minimize the likelihood of switching.

Bipolar disorders: is there an influence of seasonality or photoperiod?

“…This result agrees with recent reviews 9,38 and clinical trials. 8,14,21 Manic episodes peak during spring/summer and, to a lesser extent, in the autumn, depending on climatic variations, whereas depressive episodes peak Data presented as n (%).…”

“…Identifying patients with such susceptibilities would enable the development of personalized therapeutic strategies to prevent affective recurrences 38 or of chronotherapeutic interventions such as sleep deprivation, the blue-blocking regime in mania (''a virtual darkness therapy''), or interpersonal or social rhythm therapy.…”

Involuntary admissions in Italy: the impact of seasonality

“…Notwithstanding these limitations, in conclusion, seasonality has an important role in the psychopathology of psychiatric disorders, particularly in bipolar and related disorder. Moreover, this concept probably constitutes the basis of clinical picture at onset, appearing closely linked to the biological rhythms as sleep and circadian and seasonal environmental changes (Young & Dulcis 2015). So, we provided further evidence that seasonality has an influence on the severity of psychiatric disturbances, specifically among those characterized by a greater biological vulnerability.…”

Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features

“…These models typically reproduce aspects of hyperactivity (Shaldubina et al 2002), with some measuring impaired risk-taking (Young et al 2011b), and increased reward seeking (van Enkhuizen et al 2013c). An awareness exists for the necessity to model the full spectrum of BD (depression and mania) in animals in order to find novel treatments for the full disorder (Machado-Vieira et al 2004), but the complexity of the matter has prevented such an outcome as yet (Young and Dulcis 2015). …”