The neurobiology of the switch process in bipolar disorder: a review

Abstract

Objective: The singular phenomenon of switching from depression to its opposite state of mania or hypomania, and vice versa, distinguishes bipolar disorder from all other psychiatric disorders. Despite the fact that it is a core aspect of the clinical presentation of bipolar disorder, the neurobiology of the switch process is still poorly understood. In this review, we summarize the clinical evidence regarding somatic interventions associated with switching, with a particular focus on the biologic underpinnings presumably involved in the switch process.

Data sources: Literature for this review was obtained through a search of the MEDLINE database (1966-2008) using the following keywords and phrases: switch, bipolar disorder, bipolar depression, antidepressant, SSRIs, tricyclic antidepressants, norepinephrine, serotonin, treatment emergent affective switch, mania, hypomania, HPA-axis, glucocorticoids, amphetamine, dopamine, and sleep deprivation.

Study selection: All English-language, peer-reviewed, published literature, including randomized controlled studies, naturalistic and open-label studies, and case reports, were eligible for inclusion.

Data synthesis: Converging evidence suggests that certain pharmacologic and nonpharmacologic interventions with very different mechanisms of action, such as sleep deprivation, exogenous corticosteroids, and dopaminergic agonists, can trigger mood episode switches in patients with bipolar disorder. The switch-inducing potential of antidepressants is unclear, although tricyclic antidepressants, which confer higher risk of switching than other classes of antidepressants, are a possible exception. Several neurobiological factors appear to be associated with both spontaneous and treatment-emergent mood episode switches; these include abnormalities in catecholamine levels, up-regulation of neurotrophic and neuroplastic factors, hypothalamic-pituitary-adrenal axis hyperactivity, and circadian rhythms.

Conclusions: There is a clear need to improve our understanding of the neurobiology of the switch process; research in this field would benefit from the systematic and integrated assessment of variables associated with switching.

Figure 1. Neurobiology of the switch process: a comprehensive overview of the current evidence

Several factors have been associated with the switch process in BPD, but little is known about how these neurobiological variables are interconnected. Psychostimulants, TCAs, SNRIs and sleep deprivation, three interventions that trigger manic switches in a significant proportion of individuals with BPD, are all known to increase catecholamine levels. Increased catecholamine levels lead to upregulation of factors involved in neuroplasticity cascades and to increased post-synaptic receptor sensitivity, which might ultimately increase the liability to switch. Psychostimulants also act by activating GSK-3 and PKC, two major proteins whose inhibition is important in the mechanism of action of mood stabilizers. Other major determinants of this complex phenomenon include glucocorticoids, which increase cellular vulnerability to different physiological stressors (e.g., glutamatergic-mediated excitoxicity), abnormal glutamatergic transmission, and circadian rhythm instability. Some genetic polymorphisms that regulate catecholaminergic transmission (norepinephrine and dopamine transporters), neuroplasticity (BDNF), circadian period length (GSK-3), and GRK-3 may also be important mediators of the switch phenomenon. Abbreviations: AMPA: alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; BDNF: brain-derived neurotrophic factor; CREB: cyclic AMP response element binding protein; GRK-3: G protein receptor kinase 3; GSK-3: glycogen synthase kinase-3; PKC: protein kinase C; SNRIs: serotonin and norepinephrine reuptake inhibitors; TCAs: tricyclic antidepressants; TrkB: tyrosine receptor kinase B.