The authors concluded that cerebrolysin could improve significantly global clinical impression scores in patients with mild to moderate Alzheimer's disease. There were some limitations to this review, in particular with the reporting of review methodology, but, overall, the authors' cautious conclusion appears appropriate.

To evaluate the effectiveness of the nootropic agent cerebrolysin for the treatment of patients with mild to moderate Alzheimer's disease (AD).

The Cochrane Library, MEDLINE, PubMed and CBM-disc were searched; the search terms were reported. In addition, EBEWE Pharmaceutical Ltd was contacted for data.

Study designs of evaluations included in the review

Double-blind randomised controlled trials (RCTs) with a Jadad quality score of 3 or more were eligible for inclusion in the review.

Specific interventions included in the review

Studies that compared cerebrolysin with placebo were eligible for inclusion. Most of the included studies evaluated a treatment regimen of 30 mL/day cerebrolysin for 5 days a week for 4 weeks; some studies evaluated treatment over 6 or 12 weeks, one study repeated the 4-week treatment block after 2 months, and one study followed up the initial 4-week treatment with treatment twice weekly for 8 weeks. The included studies were conducted in Europe, China, Canada and South Korea.

Participants included in the review

Studies of male and female patients aged over 50 years and with a clinical diagnosis compatible with mild to moderate AD were eligible for inclusion. Most of the included studies diagnosed patients using the NINCDS-ADRDA criteria; other studies used these criteria in conjunction with the American Psychiatric Association's DSM criteria, while one study used DSM criteria alone. Baseline Mini-Mental State Examination (MMSE) scores ranged from 10 to 26.

Outcomes assessed in the review

Studies that measured clinical global impression, cognitive performance and activities of daily living (ADL) were eligible for inclusion. Responder rates (defined as moderate or marked improvement from baseline) were assessed using the Clinical Global Impression/Change (CGI/C) or Clinical Interview Based Impression of Change (CIBI/C); cognitive function was based on the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and the MMSE. The included studies used five different scales to assess ADL.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Only studies that were double-blind and met minimum quality criteria (a Jadad score of 3 or more) were included. The authors did not state how the validity assessment was performed.

One reviewer extracted the data. The authors stated that any disagreements were resolved with the other reviewers. For each study, the standardised mean difference (SMD) was calculated for measures of cognitive function and ADL. Log odds ratios (ORs) were used to measure differences in response rates between treatment and control interventions.

How were the studies combined?

The pooled log OR for response rates and cognitive function and the weighted SMD for ADL were calculated, along with 95% confidence intervals (CIs) were calculated. Fixed-effect models were used in the absence of significant statistical heterogeneity, and random-effects models where heterogeneity was significant.

How were differences between studies investigated?

Statistical heterogeneity was assessed using the Q-statistic (p<0.2 indicated significant heterogeneity).

Six RCTs (n=772) were included.

Responder rates based on CGI/C or CIBI/C.

Cerebrolysin was associated with a significant increase in response rates compared with control, 66.9% versus 41.8%; log OR using a random-effects model was 1.1799 (95% CI: 0.7463, 1.6135). Significant heterogeneity was found (p=0.0504).

Cognitive function.

ADAS-cog scale: there was no significant difference between cerebrolysin and control; log OR using a random-effects model was -2.01 (95% CI: -4.03, 0.01), based on 4 studies. Significant heterogeneity was found (p=0.0029). MMSE: cerebrolysin was associated with a significant improvement; log OR using a random-effects model was -0.78 (95% CI: -1.39, -0.17), based on 3 studies. No significant heterogeneity was found (p=0.2628).

ADL.

There was no significant difference between cerebrolysin and control for ADL; the SMD was 0.64 (95% CI: -1.37, 1.13), based on 5 studies. Significant heterogeneity was found (p<0.0001).

Cerebrolysin could improve significantly global clinical impression scores in patients with mild to moderate AD.

The review addressed a clear question that was defined in terms of the participants, intervention, outcomes and study design. Several relevant sources were searched, but it was not explicitly stated whether attempts were made to minimise publication and language bias. Only relatively higher quality studies that met predefined quality criteria were eligible. Methods were used to minimise reviewer errors and bias in the extraction of data, but it was unclear whether similar steps were taken at the study selection stage (and therefore the validity assessment). Significant heterogeneity was found for three of the four outcomes but potential sources of heterogeneity were not investigated. The direction of treatment effect appeared similar for response rates and cognitive function, but not for ADL. It was not reported whether the data used in the analysis were post-treatment or at the end of the follow-up period. There were limitations to this review but, overall, the authors' cautious conclusion appears appropriate.

Practice: The authors did not state any implications for practice.

Research: The authors stated the need for further research to evaluate the effects of cerebrolysin on cognitive performance and ADL.

National Natural Science Foundation of China, grant numbers 30070860 and 30371731; the Key Project of Shanghai Municipal Sciences and Technology Commission, grant numbers 03JC14064 and 34319230.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.