Bipolar disorder: The foundational role of mood stabilizers
The extent of ion dysregulation is directly associated with the expressed mood state of the illness. A small reduction in the activity of the sodium pump results in a small increase in intracellular sodium (approximately 10 mM).39,58 This led to the hypothesis that increased intracellular sodium causes the transmembrane potential to increase closer to membrane depolarization threshold, which increases excitability of affected neurons.38,39,58 Neurons are likely to fire and propagate signals more easily, which may manifest as symptoms of mania, such as increased energy, activity, lability, excitability, irritability, tangentiality, and looseness of associations. As the process of increased intracellular sodium progresses, a minority of neurons are expected to have their transmembrane potentials depolarize sufficiently for the resting membrane potential to go beyond threshold potential.59 Such neurons are in a state of constant depolarization (also known as depolarization block), which disrupts neuronal circuits. The difficulty in progression of these signals results in the classic bipolar depression symptoms of low energy, reduced activity, and slowing of all brain activity that is seen as psychomotor slowing.38
Implications for treatment
Medications for treating bipolar illness include lithium, anticonvulsants, benzodiazepines, first-generation antipsychotics, and SGAs.37,43
Mood stabilizers (lithium and certain anticonvulsants) correct the previously mentioned sodium abnormality by reducing sodium entry into the cell in an activity-dependent manner.43 As the only agents that directly address a known pathophysiologic abnormality, they are foundational in the treatment of BD.60 Lithium effectively treats acute mania and prevents relapse.61 It preferentially targets the active neurons, entering through both voltage-responsive and neurotransmitter-coupled channels.43,62 This results in an increase of intracellular lithium concentrations to as much as 8 times that of the extracellular concentration.63 These ions displace intracellular sodium ions in a 1:1 ratio, which results in a reduced intracellular sodium concentration that reduces the excitability of neurons.43,57,62
Substantial evidence supports the use of valproic acid for initial and maintenance treatment of BD.64 It inhibits the voltage-sensitive sodium channel when the channel is open, which results in an activity-dependent action that selectively impacts rapidly firing neurons.43 The voltage-gated sodium channels exist nearly exclusively on the axon, beyond the hillock65; as such, valproic acid will only inhibit neurons that fire, whereas lithium accumulates throughout the neuron and will affect depolarization in the neuronal soma as well as the firing in the axon.43 Additionally, valproic acid has been observed to enhance gamma-aminobutyric acid (GABA) levels and transmission.43,66,67 A meta-analysis that included 6 randomized controlled trials illustrated that, acutely, valproate was not different from lithium’s overall efficacy (RR 1.02; 95% CI, 0.87 to 1.20), but was associated with reduced dropout rates compared with placebo or lithium (RR 0.82; 95% CI, 0.71 to 0.95 and RR 0.87; 95% CI, 0.77 to 0.98, respectively).64
Lamotrigine is an anticonvulsant used for initial and maintenance treatment of BD, with greater efficacy for depressive episodes68; it also has notable effect for treating bipolar depression, although it is not FDA-approved for this indication.69 Lamotrigine inhibits sodium influx by binding to open voltage-gated sodium channels70 but also appears to reduce N-methyl-D-aspartate–mediated sodium entry,71 thereby acting both prehillock and posthillock.
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