In this issue of Neuropsychopharmacology, Chiu et al (2011) present preclinical data that combined administration of two widely used drugs, lithium (Li) and valproate acid (VPA), which therapeutic effects in two murine genetic models of Huntington disease (HD). HD is a dominantly inherited, adult-onset neurodegenerative disorder with prominent psychiatric manifestations. It is presently untreatable and uniformly fatal. Although uncommon, HD is an attractive target for neuroprotective therapy because a single type of mutation, expanded CAG repeats within the open reading frame of the huntingtin (htt) gene, causes all cases of HD, mutant alleles exhibit 100% penetrance, and presymptomatic carriers can be identified easily. Although htt and the characteristic mutation were discovered almost 20 years ago, the normal function of htt remains elusive. Research over the past couple of decades provides creditable evidence for several proximate mechanisms of neurodegeneration driven by mutant htt. This latter fact presents a real challenge to the development of effective therapies, as it is unlikely that targeting a single mechanism of neurodegeneration will be effective. This is a solid rationale for some form of polytherapy.

Chiu et al (2011) present a well-performed study of combination therapy with Li and VPA in preclinical HD mouse models. Distinguishing features of this study include positive results in two different models, favorable outcomes in several behavioral measures, reduction of mortality in one model, and biochemical biomarker evidence of relevant effects in brain. As Li and VPA are widely used agents in psychiatric and neurologic practice, the authors reasonably suggest that this combination should be pursued in neuroprotective clinical trials for HD.

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