Translational research in bipolar disorder: emerging insights from genetically based models

Abstract

Bipolar disorder (BPD) is characterized by vulnerability to episodic depression and mania and spontaneous cycling. Because of marked advances in candidate-gene and genome-wide association studies, the list of risk genes for BPD is growing rapidly, creating an unprecedented opportunity to understand the pathophysiology of BPD and to develop novel therapeutics for its treatment. However, genetic findings are associated with major unresolved issues, including whether and how risk variance leads to behavioral abnormalities. Although animal studies are key to resolving these issues, consensus is needed regarding how to define and monitor phenotypes related to mania, depression and mood swing vulnerability in genetically manipulated rodents. In this study we discuss multiple facets of this challenging area, including theoretical considerations, available tests, limitations associated with rodent behavioral modeling and promising molecular-behavioral findings. These include CLOCK, glycogen synthase kinase 3beta (GSK-3beta), glutamate receptor 6 (GluR6), extracellular signal-regulated kinase-1 (ERK1), p11 (or S100A10), vesicular monoamine transporter 2 (VMAT2 or SLC18A2), glucocorticoid receptors (GRs), Bcl-2-associated athanogene-1 (BAG1) and mitochondrial DNA polymerase-gamma (POLG). Some mutant rodent strains show behavioral clusters or activity patterns that cross-species phenocopy objective/observable facets of mood syndromes, and changes in these clustered behaviors can be used as outcome measures in genetic-behavioral research in BPD.

Figure 1

(a) BPD has unique episodic and dual-directional features in which mood states can be either elevated (red, mania), suppressed (blue, depression) or rapidly alternate between the two extremes (mixed episodes). Euthymic/remitted phases occur between the episodes in which patients, especially those with residual mood symptoms, remain vulnerable to the recurrence of full-blown mood episodes. Mood stabilizers, such as lithium, valproate, carbamazepine, lamotrigine, as well as atypical antipsychotics, are effective therapeutic agents that gradually relieve the symptoms of mania and/or depression. They also prevent the recurrence of mood episodes. Recent data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study found that approximately 60% of patients recover after appropriate treatments, and approximately 50% of recovered patients experience a recurrence within 2 years; recurrence is highly associated with residual mood symptoms at initial recovery. BPD-I: patient has one or more manic episodes or mixed episodes. Often individuals have also had one or more major depressive episodes. BPD-II: patient has at least one hypomanic episode and at least one major depressive episode. (b) Conceptually, the course of BPD can be divided into two major parts: vulnerability and episode stages; the illness is further characterized by a transition period from vulnerability to episode stage. Genetic variants and environmental stressors, and the interaction between the two (G × E), contribute to the predisposed abnormalities underlying the vulnerability stage. These two factors and their interaction may also contribute to the intrinsic (or spontaneous) switch mechanism. Psychosocial and biological stressors can trigger mood episodes in susceptible individuals. The use of psychostimulants and experimental monoamine depletion can cause mania or depressive relapses in subjects with a personal or family history of mood disorders, or with certain genetic variants. Unique pathophysiological mechanisms are believed to underlie depression, mania and mixed episodes. The color reproduction of this figure is available on the html full text version of the manuscript.