How does blocking voltage‑gated sodium channels affect mood, particularly in bipolar disorder?

Voltage-Gated Sodium Channels and Mood Regulation

Blocking voltage-gated sodium channels (VGSCs) stabilizes mood in bipolar disorder by reducing excessive neuronal firing, which decreases presynaptic neurotransmitter release and interrupts pathological excitatory signaling in motivational and limbic circuits. 1

Mechanism of Action on Neuronal Excitability

Voltage-gated sodium channels are responsible for the initial depolarization phase of action potentials in brain neurons. 2 When these channels are blocked:

• Action potential propagation is limited, preventing the electrical signal from traveling down the axon to the presynaptic terminal 1
• Fewer action potentials result in less calcium influx through voltage-gated calcium channels at the nerve terminal 1
• This directly decreases the release of excitatory neurotransmitters into the synaptic cleft 1

Impact on Mood Circuits in Bipolar Disorder

The therapeutic effect in bipolar disorder operates through multiple neurobiological process domains:

• Motivational circuit modulation: Genetic variants in ion channel genes perturb motivational circuits, leading to aberrant reward processing and poor impulse control that characterize manic episodes 3
• Disruption of pathological excitability cycles: In chronic neuropsychiatric conditions like bipolar disorder, prolonged neuronal activation sensitizes both presynaptic and postsynaptic neurons; VGSC blockade interrupts this maladaptive cycle 1
• Restoration of excitability balance: Multiple environmental triggers can disrupt neuronal excitability balance through activity-dependent molecular processes, and sodium channel blockers help restore this balance 3

Clinical Evidence for Mood Stabilization

Carbamazepine and oxcarbazepine are the preferred sodium channel blockers for mood stabilization, demonstrating dramatic therapeutic responses. 4, 5

Key clinical considerations:

• Low doses are typically effective: Approximately 85% of patients with paroxysmal neurological conditions achieve complete remission with carbamazepine 50-200 mg/day or oxcarbazepine 75-300 mg/day 4
• Rapid onset of action: Therapeutic effects can be observed within the first week of treatment 4
• Mechanism differs from other mood stabilizers: Unlike GABA-ergic drugs or levetiracetam (which works through SV2A), sodium channel blockers specifically limit action potential propagation 1, 6

Neurobiological Endophenotypes Affected

Sodium channel blockade impacts specific measurable endophenotypes in bipolar disorder:

• Altered frontolimbic connectivity is normalized through reduced excitatory transmission 3
• Increased amygdala activity during mood episodes is dampened 3
• Circadian neuronal rhythms are stabilized, addressing sleep disturbances 3
• Energy regulation is improved through effects on ATP shuttling 3

Critical Pharmacological Distinctions

Carbamazepine induces cytochrome P450 enzymes, leading to decreased blood levels over time and significant drug-drug interactions, requiring dose adjustments during chronic therapy. 1 This distinguishes it from lamotrigine and other newer sodium channel blockers.

The FDA label for oxcarbazepine notes that cognitive/neuropsychiatric adverse reactions occur in 7.1% of treated patients versus 4% on placebo, with dose-related risks for somnolence (26% vs 12%) and ataxia (28.7% vs 6.4%). 5 However, lamotrigine and other VGSC blockers generally do not result in clinically meaningful impairment with chronic administration. 1

Selectivity and Future Directions

Conventional sodium channel blockers lack subtype selectivity, which drives current research toward more precise therapeutic agents. 7 Different sodium channel subtypes (Nav1.1, Nav1.2, Nav1.6) have distinct roles:

• Nav1.1 mutations predominantly impair interneuron function, leading to decreased inhibition rather than increased excitation 8
• This suggests that selective targeting of specific sodium channel subtypes could provide more refined mood stabilization with fewer side effects 7

Structural Basis for Drug Action

The binding sites for sodium channel blockers have been elucidated through bacterial channel crystal structures, revealing that these drugs bind within the channel pore and stabilize the inactivated state. 9 This structural understanding explains their voltage- and frequency-dependent inhibition, making them particularly effective at suppressing rapid, repetitive firing characteristic of manic episodes while having less effect on normal neuronal activity. 2, 9