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 myoinositol 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.