Membrane Stabilization Citicoline

Citicoline (Interneuron Pharmaceuticals) is an exogenous form of cytidine-5'-diphosphocholine (CDP-choline), used in membrane biosynthesis. Citicoline appears to reduce ischemic injury, both by stabilizing membranes and by decreasing free radical formation. Citicoline is an approved stroke treatment medication in several countries. A Phase 2 United States trial found improved outcome in stroke patients treated with 500 mg of citicoline (32). A Phase 3 trial was then conducted to confirm efficacy. This trial randomized patients in a 2:1 fashion to receive either 500 mg of citicoline (n = 267) or placebo (n = 127) orally in capsule form every day for 6 weeks (33). Treatment was started within 24 hr of symptom onset. Overall, no significant differences were seen between the groups on any of the planned assessments of functional outcome at 3 months. Citicoline was well tolerated, with few, if any, side effects. However, a post hoc subgroup analysis did suggest that patients with more severe strokes (NIHSS > 8) might have had better functional outcome when treated with citicoline. A second 900-patient Phase 3 trial was then conducted that involved only moderate to large strokes. Unfortunately, the company chose a novel endpoint (NIHSS score improvement > points), and the trial was negative. Had they used more conventional endpoints (NIHSS=0 or 1, mRS=0 or 1, etc.), the trial would have been positive (34). A meta-analysis of all US citicoline trials was performed. For the 1372 patients treated within 24 hr, with NIHSS > 8, the chance of excellent recovery (global outcome measure) at 3 months was 27.2%, citicoline, versus 20.2%, placebo (p < 0.001) (35), a 7% absolute and 35% relative improvement over placebo.

No further trials are planned, which is unfortunate, as it appears to have a modest benefit and no side effects. Interestingly, CDP-choline is available as a supplement (Jarrow Formulas, Inc.), available through the Internet. The cost is approximately $40 per month for a suggested 1000 mg/day dose.

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