The efficacy and safety of animal-derived nootropics in cognitive disorders: Systematic review and meta-analysis

Abstract

Background: The animal-derived nootropics, Cerebrolysin, Actovegin and Cortexin, may have potential in treating neurocognitive disorders. Although these drugs have international usage, reports on their efficacy have been conflicting. These agents have been suggested for all dementia types, but may have particular utility in vascular cognitive impairment (VCI). We used systematic review and meta-analyses to summarize evidence of efficacy in all cause dementia, with a subgroup analysis restricted to VCI.

Methods: We searched multidisciplinary, electronic databases from inception to August 2020. We assessed risk of bias using the Cochrane tool and framed results using GRADE criteria. We used random effects models to create summary estimates. Our primary outcome was change in cognition based on any quantitative cognitive assessment scale using standardized mean difference (SMD). We assessed various secondary efficacy outcomes and a safety outcome of serious adverse events. We performed subgroup analyses limited to VCI.

Results: Summary estimates suggested Cerebrolysin was potentially beneficial in improving cognition (8 trials,793 participants, SMD:-0.16, 95%CI:-0.30 to -0.03) and global function (4 trials,479 participants, OR:2.64, 95%CI:1.17 to 5.98) in the short term. There was no difference in incidence of serious adverse events (6 trials,1014 participants, RR:0.96, 95%CI:0.78 to 1.18). In our VCI subgroup, results were similar to the main analysis, with a beneficial effect on cognition (SMD:-0.22, 95%CI:-0.42 to -0.03) and clinical global impression (OR 2.99, 95%CI:1.02 to 8.73). The limited number of eligible studies for Actovegin (n = 2 trials,563 participants) and Cortexin, (n = 1 trial,80 participants) precluded meta-analyses but data suggested potential efficacy and no safety concerns. Across all included studies, risk of bias was moderate to high, there was imprecision, and certainty of evidence was considered low to very low.

Conclusion: Although published data suggest potential benefits and relative safety of animal derived nootropics, the supporting evidence is weak. The size of the effects demonstrated were modest and probably less than would be considered clinically relevant.

Keywords: Actovegin; Cerebrolysin; Cortexin; Dementia; Systematic review; Vascular Cognitive Impairment.

Fig. 1

Prisma flow diagrams describing details of the Cerebrolysin (A), Actovegin (B), and Cortexin (C) studies selection process.

Fig. 2

Summary of risk of bias ratings of each bias domain for each included Cerebrolysin (A), and Actovegin (B) trials.

Fig. 3

Forest plots comparing the change of various outcomes from baseline in patients receiving Cerebrolysin (30 ml/day) vs. placebo. Cognitive function short term effects (A); Cognitive function medium term effects (B); clinical global impression(C); BPSD (D); ADL (E); the incidence of serious adverse events (F).

Fig. 4

Forest plots comparing the change of various outcomes from baseline in patients with vascular cognitive impairment receiving Cerebrolysin vs. placebo, at the final follow-up visit. Cognition (A); global function(B); BPSD (C); ADL (D); the incidence of serious adverse events (E).