Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness

Objective: The most widely accepted hypothesis regarding the mechanism underlying lithium's therapeutic efficacy in manic-depressive illness (bipolar affective disorder) is the inositol depletion hypothesis, which posits that lithium produces a lowering of myo-inositol in critical areas of the brain and the effect is therapeutic. Lithium's effects on in vivo brain myo-inositol levels were investigated longitudinally in 12 adult depressed patients with manic-depressive illness. Method: Medication washout (minimum 2 weeks) and lithium administration were conducted in a blinded manner. Regional brain myo-inositol levels were measured by means of quantitative proton magnetic resonance spectroscopy at three time points: at baseline and after acute (5-7 days) and chronic (3-4 weeks) lithium administration. Results: Significant decreases (approximately 30%) in myo-inositol levels were observed in the right frontal lobe after short-term administration, and these decreases persisted with chronic treatment. The severity of depression measured by the Hamilton Depression Rating Scale also decreased significantly over the study. Conclusions: This study demonstrates that lithium administration does reduce myo-inositol levels in the right frontal lobe of patients with manic-depressive illness. However, the acute myo-inositol reduction occurs at a time when the patient's clinical state is clearly unchanged. Thus, the short-term reduction of myo-inositol per se is not associated with therapeutic response and does not support the inositol depletion hypothesis as originally posited. The hypothesis that a short-term lowering of myo-inositol results in a cascade of secondary signaling and gene expression changes in the CNS that are ultimately associated with lithium's therapeutic efficacy is under investigation.