Pharmacological agents under research for the maintenance treatment in bipolar disorder.

The treatment of bipolar disorder is a current challenge for clinicians and despite progress in psychopharmacology, options remain limited and results are often unsatisfactory. Current research focuses on finding new pharmaceutical agents for all phases of bipolar disorder, i.e. mania, bipolar depression and maintenance. Particularly, relapse prevention and longterm stabilization is a major therapeutic target. Combination treatment and polypharmacy are the most common choices concerning relapse prevention. Furthermore, during maintenance phase patients often experience residual mood symptoms, cognitive deficits and functional decline, which altogether illustrate the inadequate effectiveness of existing treatments and the need for new, targeted, effective and safe treatments for bipolar disorder. This review focuses on active agents for maintenance treatment in bipolar disorder investigated during the last 5 years. The compounds under investigation have been tried or tested either as monotherapy or as an add-on treatment in clinical trials that have progressed up to phase 3 or in preclinical models of bipolar disorder. While awaiting the completion of many ongoing studies, the results so far indicate that paliperidone and pregabalin may have a position in the maintenance treatment of bipolar disorder. Additionally, dextromethorphan, which acts primarily as a NMDA antagonist, may be an interesting compound for further study. However, results on memantine, another NMDA antagonist, were not encouraging. The effects of omega-3 fatty acids and cytidine were not superior to placebo, although they both have neurotrophic and neuroprotective properties. Eslicarbazepine, which has antiepileptic action, provided some evidence of efficacy as monotherapy. Regarding preclinical studies in experimental models, the pharmacological agents under investigation seem to follow the neurobiological pathways related to mechanism of action of lithium, which is still the "golden standard" for preventing recurrence in bipolar disorder. Major therapeutic targets are synthetic glucose kinase 3 (GSK-3) and the path of phosphoinositol (IMP), both probably involved in the action of lithium. Furthermore, the role of circadian rhythms maintenance is being studied in preclinical and clinical trials investigating the efficacy and safety of compounds CK-01 and ramelteon, respectively. Research also focuses on pharmacological agents based on epigenetic changes and gene expression modulation, as the inhibitor of histone deacetylase (HDAC). Of note, the development of valid and reliable experimental models for bipolar disorder, which currently remains quite controversial, will contribute to the understanding of the pathogenic mechanisms and the development of new effective treatments. Improving methodology aspects of clinical trials, such as diagnosis, clinical heterogeneity, monitoring time, gender differences and comorbidities, may promote research. Current studies seem promising for the development of novel pharmacological agents in the near future, although there are methodological limitations in the search for the maintenance treatment in bipolar disorder. New therapeutic targets include not only the already known mechanisms of action, but also novel pathophysiological pathways, probably implicated in bipolar disorder.