PKC in mania
Biochemical data support the possible connection between PKC and the pathophysiology and treatment of BD. Friedman and colleagues9 studied PKC activity and PKC translocation in response to serotonin in platelets collected from patients with BD before and during lithium treatment. They found that the ratios of platelets membrane-bound to cyto- solic PKC activity were increased in participants during a manic episode.9

In a postmortem study, the same group10 found increased PKC activity and translocation in the brains of patients with BD compared with controls.

Studies have also shown that PKC signaling pathways are altered after treatment with lithium or valproate.4,9,11-13 Long-term treatment with lithium in rats resulted in a significantly decreased PKC stimulation-induced release with phorbol esters in the cortex, hypothalamus, and hippocampus. PKC isozymes a and e were reduced in the frontal cortex and hippocampus following lithium administration.13 Similarly, valproate was also found to cause an isozyme-specific decrease in PKC a and e.4

Furthermore, studies have shown that stimulants, such as amphetamine, which are capable of triggering manic episodes in susceptible individuals and which induce manic-like behaviors in rodents,14 activate PKC and growth-associated protein (GAP)-43 phosphorylation (implicated in neurotransmitter release).15-18 Given the compelling biochemical data, a number of behavioral studies have been undertaken to validate the role of PKC in mania-related behaviors.

In rodents, the PKC inhibitor tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity, and it normalized amphetamine-induced increases in visits to the center of an open field (representing risk-taking behavior); tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43.14 PKC activity is increased in the prefrontal cortex following exposure, and the ability of the prefrontal cortex to regulate emotion, thought, and action is markedly impaired by overactivity of PKC sig- naling.19 In toto, the evidence suggests that pharmacological or stress-induced activation of PKC in animals results in many of the behavioral changes seen in mania, such as hyperactivity, risk-taking behavior, and increased hedonic drive. Its inhibition attenuates these same behavioral changes in a manner similar to that of mood stabilizers on acute mania.

These data strongly suggested that further study of PKC inhibitors in humans with BD was indicated. When the decision was made to further validate this target in humans, tamoxifen was the only relatively selective PKC inhibitor available to test. Tamoxifen, a synthetic antiestrogen widely used in the treatment of breast cancer, has a favorable adverse-effect profile compared with other chemotherapeutic agents20; considerable data exist on its safety profile and ability to cross the blood-brain barrier.

Finally, the exciting recent identification of a bipolar susceptibility gene that is an upstream regulator of PKC has strengthened the potential role of PKC signaling pathway in the pathophysiology of BD. For example, 2 recent, independent genome-wide association studies identified diacylglycerol (DAG) kinase e (DGKH) as a gene associated with higher risk of BD.21 DGKH is a major regulator of DAG, which activates all known classic and novel isoforms of PKC.

PKC inhibitors: novel therapeutics for acute mania?
Based on the data generated since the 1990s, researchers embarked on proof-of-concept studies with tamoxifen for acute mania. The first study included 7 patients (5 male and 2 female) with acute bipolar mania.22 Participants were inpatients or outpatients aged 18 to 65 years with a diagnosis of bipolar mood disorder manic episode based on a DSM-IV structured clinical interview. Tamoxifen resulted in a significant decrease in manic symptoms as rated by the Young Mania Rating Scale (YMRS), with a mean decrease of 10 points. In addition, 71% of patients met response criteria (ie, a 50% decrease in the YMRS score from baseline).

In a double-blind, placebo-controlled monotherapy pilot trial in patients with bipolar mania, tamoxifen was found to have significant antimanic effects as early as day 5 and throughout the 3 weeks of the trial.23 Very recently, these studies were replicated in a larger placebo-controlled study.24 These studies confirm the hypothesis that directly inhibiting PKC improves manic symptoms. It is important to emphasize that while these findings are encouraging, the results are preliminary and based on fairly small sample sizes; the results need to be confirmed in larger studies involving several hundred participants and with more selective PKC inhibitors.

Nonetheless, this strategy illustrates that it is possible to develop a drug to treat a specific disorder; in this case, the illness was BD, for which no novel mechanism of action had ever been identified and proved in clinical studies.

The evidence to date on multiple levels (ie, preclinical, clinical) supports further study of PKC inhibitors in BD. Other selective PKC inhibitors are currently in phases 1 through 3 of development for treatment of a variety of conditions (eg, diabetic complications) and are possible candidates to test in BD.25 Naturally, issues regarding PKC isoform selectivity, brain penetrance, and short- and long-term tolerability will need to be examined.

Finally, a point that merits further discussion is our need to integrate current technologies with the drug evaluation process in proof-of-concept studies. The importance of identifying endophenotypes in complex neuropsychiatric disorders has been reviewed elsewhere.26 Briefly, endophenotypes can be conceptualized as quantifiable components along the pathway between phenotype of disease and distal genotype. An endophenotype may be biochemical, neuropsychological, endocrinological, neuroanatomical, cognitive, or neurophysiological (eg, seen in magnetic encephalography, polysomnography) in nature.

These new investigational tools are beyond the scope of this review. We note them, however, because they may have considerable utility in predicting phenomena such as time to response, remission, and degree of improvement. Given our current inability to predict who will respond to which medication and within what time frame, the evaluation of characteristics observed using valuable new technologies may provide a better understanding of the neurobiological basis involved in symptom improvement, and it also may allow for the identification of surrogate outcomes and molecular targets for the next generation of treatments. Indeed, such strategies are being increasingly used in our study of complex neuro-behavioral medical illnesses.

Concluding thoughts
Thus, there is now strong evidence to support the view that targeting intracellular signaling cascades is a useful strategy in drug development for BD. The use of modulators of ubiquitous kinases in the CNS, however, is met with some trepidation because of possible problems in specificity, tolerability, and safety. At present, many kinases are in the early stages of drug development for diverse medical illnesses.27 It should be emphasized that while appropriate concerns regarding these compounds are in order, lithium is a drug that targets multiple signaling cascade molecules, has been found to be generally safe, and has been a primary therapeutic used for BD for more than half a century. This latter point illustrates that it may, indeed, be possible to develop safe and effective signaling system modulators for CNS illnesses.

We believe that the strategy of drug development research we have described here will, in due course, result in noticeably improved therapeutics for psychiatric illnesses.

 
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