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.

Keywords: Bipolar disorder; Catecholamines; Depression; Mania; Seasonality; Switching; Triggers.

Figure 1. Symptoms of the extreme states of bipolar disorder, mania and depression

Bipolar disorder is a unique disorder that transcends domains of function because the same patient can exhibit depression or mania at different points in their life. Periods when they exhibit symptoms of neither state are referred to as euthymia. Some symptoms are on a scale (yellow arrows) whereby the symptoms of each state are on the opposite ends of the spectrum. Some symptoms do not link with each other, where deficits seen in a manic state are normal during depression (e.g., sensorimotor gating as measured by prepulse inhibition). Importantly, identifying triggers that change the neural circuitry of the brain toward mania or depressive symptoms is a vital step toward delineating the key circuitry that allows for a hypersensitivity to such triggers.

Figure 2. Photoperiod length-induced changes of mood

As sufferers of bipolar disorder enter spring/summer, where longer light-induced active periods are present, they are more likely to exhibit mania symptoms. During shorter light-induced inactive periods however, bipolar sufferers are more likely to exhibit depressive symptoms. Maintaining stability of photoperiod supports a euthymic, non-clinical state, consistent with psychosocial social rhythm therapy, timed light exposure, and sleep pattern stabilization treatments.

Figure 3. Schematic model of photoperiod-induced neurotransmitter switching and receptor matching as occurs in nocturnal rats

Activation of the retino-hypothalamic projection (RHP) during a short-activity (19L:5D) photoperiod shifts transmitter expression in PaVN neurons to somatostatin (SST) while a long-activity (5L:19D) photoperiod shifts transmitter expression to dopamine. Dopamine type-2 receptor (D₂R) expression on corticotrophin releasing factor (CRF) cells changes in parallel with changes in dopamine expression while SST type-2,4 receptor (SSTR_2,4) expression remains constant.