This systematic review has several quality indicators: (1) The study protocol was previously registered and therefore the study appears free of selective reporting bias (reporting what is convenient for us). (2) It is reported according to the PRISMA guidelines, so the report aims to be transparent and reproducible. (3) It is based on clinical trials and therefore will not be affected by confounding of effects. (4) It combines effects using a more robust random effects model. (5) Its wording is cautious, tentative, warning of the steps needed before proposing a particular intervention ("there is a case for further clinical trials").

I have not found mention of the clinical value for patients of the main result: a standardised mean difference of 0.14, with CI [confidence interval] from 0.03 to 0.25. This means that the effect is about one seventh (0.14) of the usual differences between individuals. A very very small effect, therefore. As this is opinionated, my disappointment is that it does not dispute this.

That said, the main result (and most secondary analyses) has a curious value of the I2 statistic, which they round to 0%, implying an implausible homogeneity of effect. This invites a careful reanalysis of these results.

Michael C.B. David of Imperial College London coordinated this systematic review and meta-analysis of the cognitive and affective effects of noradrenergic drugs in patients with Alzheimer's disease. The methodology of this type of study is very robust, as it allows the results of multiple clinical studies to be consolidated and provides data from a very large sample of patients (1811 patients in this case), which would be practically impossible to obtain in conventional clinical trials. On the other hand, the problem derived from this type of methodology is whether a correct search strategy has been used in the selection of the studies analysed. If this is not the case, the results would be completely flawed, but this does not seem to be the case.

Alzheimer's disease is currently the most prevalent neurodegenerative disease and there is no effective treatment to cure this pathology. The drugs available make the disease progress more slowly, acting on a neurotransmitter system (cholinergic), which is different from the one analysed in this study, the noradrenergic, although there is evidence of an alteration of these nerve pathways also in Alzheimer's, closely related to some symptoms that these patients may experience, such as affective and depressive symptoms or cognitive alterations. For this reason, trying to improve the noradrenergic communication of these neurons could lead to an improvement in cognitive function and apathy in these patients.

The authors have contemplated some possible limitations, such as the scientific quality of the studies included in the systematic review and report that only 6 of the 19 included studies were rated as "good". In addition, it is very difficult to establish the evolutionary grade of the patients in order to establish homogeneous study subgroups and, therefore, the response to medication may be very disparate. Finally, some of the drugs analysed in the study have, in addition to their noradrenergic action, other different biological activities, also acting on dopaminergic or serotonergic neurotransmitter pathways. This fact also distorts, and is very difficult to evaluate, the final results obtained.

There are drugs that have been tested that do not only have a noradrenergic action.

If we consider that a quarter of patients with Alzheimer's disease also show a comorbid depressive disorder, it is easy to understand that the symptomatology analysed in this study is of great clinical relevance. And the results show that these types of cognitive and affective symptoms seem to improve with noradrenergic medication. But it should be borne in mind that these drugs, from very different families (there are antidepressant agents or drugs used for the treatment of attention deficit hyperactivity disorder), are not officially approved by regulatory agencies for use in Alzheimer's disease and have no effect on the main symptom of the disease, which is memory loss, as well as on the prognosis and evolution of the disorder. Their efficacy will have to be demonstrated in clinical trials specific to each of them. However, this study opens the door to progress in this direction.