The Na,K-ATPase Hypothesis for Bipolar Disorder: Implications of Normal Development

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Abstract
The Na,K pump is the indispensable component of excitable tissue that maintains transmembrane ion-based potentials. Adequate human data regarding the developmental trends in Na,K pump activity in childhood are unavailable, but human nonneuronal and animal studies demonstrate a developmental shift toward declining Na,K pump activity with increasing age. The decline in pump activity is paralleled by an age-related increase in intracellular sodium ions and a concomitant decrease in intracellular potassium ions. These changes appear to decrease the potential difference across neuronal membranes with advancing age, suggesting an increase in neuronal excitability. The Na,K-ATPase hypothesis of bipolar disorder proposes that manic symptoms are related to a modest decrease in Na,K pump activity and a consequent increase in neuronal excitability, whereas bipolar depression is consequent to a greater decrease in pump activity and a resultant decrease in neurotransmitter release. Changes in ion transport and distribution with age may offer an explanation for clinical observations of developmental variations in lithium response, including the apparent agerelated decline in maximal pretoxic lithium level, decline in therapeutic blood level range, and perhaps an increase in the therapeutic efficacy of lithium. The clinical implications of the hypothesis regarding the course of bipolar disorder would include an explanation of the increasing frequency and severity of episodes with advancing age. The hypothesis makes numerous predictions which are testable and suggests new avenues of pharmacological intervention.