Mood-stabilizing drugs: Are their neuroprotective aspects clinically relevant?

The possibility that there may be subtypes of bipolar disorder and the slow progress in understanding the therapeutic mechanism for approved mood-stabilizing drugs make the challenges of intelligent drug design seem daunting. Nonetheless, the numerous shortcomings in current pharmacotherapy underscore the need to develop novel therapies. There are significant problems with currently approved mood-stabilizing drugs: 1. Up to 40% of patients fail to respond to monotherapy with either lithium or valproic acid. 2. Common use of polypharmacotherapy increases the side effects associated with treatment [101]. 3. Treatment must continue for weeks to months for therapeutic effects to be greater than placebo. 4. Up to 60% of patients will discontinue therapy, which is somewhat attributable to unwanted side effects [102]. Thus, it is critical that new medications without these problems be developed for bipolar disorder. The hypothesis that mood-stabilizing drugs are neuroprotective is an important first step in new drug development. To determine if the clinical efficacy of mood-stabilizing drugs is dependent on the neuroprotective or neurogenic properties of these medications, greater strides need to be made in relating findings from cell culture and animal models to human imaging and pathology. Mounting evidence supports the neuroprotective and neurogenic properties of lithium and valproic acid in a variety of cell-culture models. It is important for clinical, biochemical, and in vitro differences between these medications to be examined, not ignored, because these differences may reveal critical distinctions between the neural mechanisms of these drugs. Continuation of the in vitro work will aid in the understanding of the mechanism by which these drugs are neuroprotective, but such studies do not advance the understanding of whether these effects are critical for the clinical efficacy of these medications. In attempting to understand the in vivo effects of these medications, a variety of evidence supports the neuroprotective and neurogenic aspects of lithium and valproic acid in healthy rodents and animal models of gross brain insult. More work needs to be done to assess whether these effects occur in animal models for bipolar disorder. The proof of principle for supporting the claim that the neuroprotective or neurogenic properties are important clinically will come from longitudinal clinical studies that compare brain morphology and function before and during treatment. If enough evidence supports the hypothesis that the neuroprotective and neurogenic properties of mood-stabilizing drugs are important for their clinical efficacy, new medications that are more efficacious and have fewer side effects will be designed based on this discovery.