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Combination Therapy in Alzheimer’s Disease

A Review of Current Evidence

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Abstract

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer’s disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of six agent classes already exist, all of which are approved for clinical use and are either already being tested or ready for phase III clinical trials for the treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA receptor, antioxidants or blockers of oxidative deamination (including Gingko biloba), anti-inflammatory agents, neurotrophic factors (including hormone replacement therapy and drugs acting on insulin signal transduction) and antiamyloid agents (including cholesterol-lowering therapy). These approaches hold promise for disease modification and have a potential to be used as combination therapy for cognitive enhancement.

Presently, only nine clinical studies have been published that have investigated the effects of a combination regimen on cognitive performance or AD. Among those, one study was conducted in elderly cognitively intact persons; the others involved patients with AD. Only five of the treatment studies followed a randomised, controlled design. Not all studies favoured the superior efficacy of combination therapy over monotherapy. Some studies, however, showed some evidence for synergistic combination effects of symptomatic therapy, including delay or prevention of disease progression in AD patients. In addition, six studies investigated the effects of AChE inhibitor in combination with antipsychotic or antidepressant therapy on behavioural aspects of AD symptomatology. In four of those studies there were indications that combination therapy had greater efficacy over monotherapy.

The treatment of AD patients requires optimised options for all stages of illness based on the available drugs. There is a great need for further well designed studies on combination therapy in AD.

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Acknowledgements

This publication is part of the German Research Network on Dementia and was funded by the German Federal Ministry for Education and Research (grant O1 GI 0102). B. Schmitt has received contracts or honoraria from Lundbeck. L. Frölich has been a consultant to and has received research grants or contracts and honoraria from Merz Pharmaceuticals, Johnson & Johnson, Janssen, Novartis, Pfizer, Eisai and Wilmar Schwabe, manufacturers and marketers of drugs used for Alzheimer’s disease or dementia. T. Bernhardt has received contracts or honoraria from Pfizer. I. Heuser and H-J. Moeller have received grants, honoraria and contracts from all major manufacturers and marketers of drugs for Alzheimer’s disease or dementia.

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  1. Division of Geriatric Psychiatry, Central Institute of Mental Health Mannheim, University of Heidelberg, Mannheim, J5, D-68072, Germany

    Beate Schmitt, Tanja Bernhardt &  Lutz Frölich

  2. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany

    Hans-Juergen Moeller

  3. Department of Psychiatry and Psychotherapy, Humboldt University, Berlin, Germany

    Isabella Heuser

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Correspondence to Lutz Frölich.

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Schmitt, B., Bernhardt, T., Moeller, HJ. et al. Combination Therapy in Alzheimer’s Disease. CNS Drugs 18, 827–844 (2004). https://doi.org/10.2165/00023210-200418130-00001

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