Physiopathology of bipolar disorders: what has changed in the last 10 years? Fisiopatologia do transtorno afetivo bipolar: o que mudou nos últimos 10 anos?

Bipolar Disorder (BD) is a chronic illness that affects approximately 1.6% of the population1 and represents one of the main causes of incapacitation worldwide.2 In the last 10 years, BD has been shown to be a heterogeneous disorder, with wide variations in symptomatology and course.3 Despite the advances in research methods used in biological psychiatry and the current knowledge of the mechanisms of mood stabilizer action, BD pathophysiology is still far from being completely understood. The initial theories regarding BD pathophysiology focused specifically on the system of neurotransmission of biogenic amines.4 The behavioral and physiological manifestations of BD are complex and undoubtedly mediated by a chain of interconnected neural circuits. Therefore, it is not surprising that the brain systems which received greater attention in neurobio logical s tudies of mood disorders were the monoaminergic systems, since these are extensively distributed in the limbic-striatal circuits of the prefrontal cortex, regions which control the behavioral manifestations of mood disorders.5 Initially, it was hypothesized that depression and mania would result from decreased transmitter transport in the presynaptic neuron or synaptic vesicles. The synaptic vesicles, acting as “buffer” systems, would not be able to fully perform their function, and, as a consequence, neurotransmitter deficit and overflow would not be satisfactorily counterbalanced. The resulting greater transmitter fluctuation in the synaptic cleft could therefore be responsible for mood swings.1 However, BD models focused on a s ingle neurot ransmit ter or neuromodulator system cannot fully explain the diverse clinical presentations of this disorder. It has been demonstrated that mood regulation involves the interaction of multiple systems and that most effective drugs probably modulate the functional balance between the various interactive systems rather than acting on a specific, isolated neurotransmission system.6 Complex interactions between semiindependent neural systems, working in harmony, are necessary for maintaining appetite and sleep patterns, as well as for stabi l iz ing body weight and l ibido, al l of which are neurovegetative functions that are typically altered in mood disorders.7 In fact, postmortem studies have shown a significant decrease in glial cells in the prefrontal cortex and limbic system, as well as fewer neuronal cells in the prefrontal cortex and hippocampus, of individuals with BD,8 supporting findings regarding anatomical and functional changes observed in neuroimaging studies.9 Furthermore, pharmacological studies have confirmed the neuroprotective activity of mood stabilizers in a series of neurotoxicity models.10 Recent research has shown that the therapeutic action of these drugs involves the regulation of various intracellular signaling systems, second messengers and gene expression.11 Physiopathology of bipolar disorders: what has changed in the last 10 years? Fisiopatologia do transtorno afetivo bipolar: o que mudou nos últimos 10 anos?