Uncertainty about the efficacy of hydergine in dementia

Hydergine has been used to treat patients with either dementia, or 'age-related' cognitive symptoms. Hydergine may offer benefit to some patients, possibly at doses of 4.5 to 9.0 mg per day, with possibly greater benefit to younger subjects and inpatients. The statistical evidence for efficacy in 'possible or probable Alzheimer's disease' patients was so modest however that one additional statistically non-significant trial would have reduced the results to non significance; evidence for efficacy in vascular dementia rested on relatively stronger effects for hydergine on clinical ratings; and effective doses may be higher than 3 mg/d (i.e., than that currently approved in the USA). Despite its availability for 40 years, the circumstances of hydergine's efficacy in dementia syndromes have not been adequately researched, and have yet to be precisely defined.

Authors' conclusions: 

As in an earlier systematic review, we found hydergine to show significant treatment effects when assessed by either global ratings or comprehensive rating scales (based here on a smaller set of trials than in the earlier published systematic review because trials were required to have data that could conform with MetaView, the Cochrane Collaboration statistics software). The small number of trials available for analysis, however, limited the ability of subgroup analyses to identify statistically significant moderating effects.

Unfortunately, most of the randomized, double-blind, and placebo-controlled trials of hydergine were conducted and published before the advent of consensus-based diagnostic standards of dementia in 1984; therefore diagnostic criteria were less specific. As a result, uncertainty remains regarding hydergine's efficacy in dementia.

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Currently hydergine is used almost exclusively for treating patients with either dementia, or 'age-related' cognitive symptoms. Since the early 1980s there have been over a dozen more clinical trials, yet hydergine's efficacy remains uncertain. Although previous reviews offer generally favourable support for hydergine's efficacy, they were, however, limited by a bias with respect to the particular clinical studies chosen (e.g., the inclusion of case reports, and uncontrolled trials), and by authors' impressionistic assessments of results. Not surprisingly, there has been a lack of consensus among reviewers with regard to the efficacy of hydergine.

In 1994, a meta-analysis was published by the present reviewers who reported that overall, hydergine was more effective than placebo. However they also observed that the statistical evidence for efficacy in 'possible or probable Alzheimer's disease' patients was so modest that one additional statistically non-significant trial would have reduced the results to non-significance.


Because of uncertainty surrounding the efficacy of hydergine, the goals of this overview were to assess its overall effect in patients with possible dementia, and to investigate potential moderators of an effect.

Search strategy: 

The trials were identified from a searches of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources on 2 March 2009 using the terms hydergin*, ergoloid* and dihydroergo*. Two proprietary databases were also searched. Published reviews were inspected for further sources.

Selection criteria: 

Trials to be included must be randomized, double-blind, parallel-group, and unconfounded comparisons of hydergine with placebo for a treatment duration of greater than one week in subjects with dementia or symptoms consistent with dementia.

Data collection and analysis: 

Data were extracted independently by the reviewers, pooled where appropriate and possible, and the pooled odds ratios (95% CI) or the average differences (95% CI) were estimated. Where possible, intention-to-treat data were used.

Outcomes of interest included clinical global impressions of change and comprehensive rating scales. Potential moderating variables of a treatment effect included: inpatient/outpatient status, trial duration, age, sex, medication dose, publication year, and diagnostic grouping.

Main results: 

There were a total of 19 trials that met inclusion criteria and that had data sufficient for analysis.

Thirteen trials reported sufficient information to use a global rating of improvement and nine trials provided information on a comprehensive rating scale. Three trials provided both outcome measures.

It was not possible to use many of the published results in a combined analysis owing to the lack of sufficient data to perform statistical analyses.

For the 12 trials that used global ratings, there was a significant effect favouring hydergine (OR 3.78, 95% CI, 2.72 to 5.27). For the nine trials that used comprehensive ratings, there was a significant mean difference favouring hydergine (WMD 0.96, 95%CI, 0.54 to 1.37).

Hydergine was well tolerated in these trials, with 78% of randomized subjects available for data analyses.

Greater effect sizes on global ratings were associated with younger age, and possibly higher dose, although most of the subgroup analyses were statistically insignificant.