48 Eventually, genetic approaches will sharpen the research for abnormal clocks by leading to an understanding of the proteins synthesized under the direction of those genes. The second hypothesis relevant to recurrence, as discussed previously, is the kindling paradigm. As advanced by Robert Post,49 this theory builds on the physiological finding that in the limbic system, intermittent subthreshold electrical or chemical stimuli produce increasingly strong neuronal depolarization; such depolarization can lead

to an independent permanent Inhibitors,research,lifescience,medical learn more seizure focus, with possible behavioral effects roughly analogous to mood disorders. Thus, kindling is a process in which a highly regulated system, with multiple feedback loops, shows an escalating response to a repetitive stimulus, reaching a point where the stimulus is no longer needed for the disturbance to continue. Post drew an analogy between this phenomenon of kindling in the nervous system and the clinical observation

Inhibitors,research,lifescience,medical (originally made by Kraepelin and confirmed in later more quantitative studies by Post and others) that external stress appears to activate early episodes of illness, but eventually the illness seems to take on a life of its own, with later episodes often occurring without precipitating stressors. In other words, both kindling Inhibitors,research,lifescience,medical and bipolar illness seemed to be processes of initial activation giving way, over time, to a self-driven process. We have reviewed the Inhibitors,research,lifescience,medical clinical psychiatric literature relevant to assessing some of the predictions of the kindling hypothesis in detail elsewhere.50 In that review, we noted that the majority of the studies support the kindling hypothesis, although with some caveats. Many were retrospective and limited to assessing hospitalized episodes of bipolar disorder. Thus, their

results may not apply Inhibitors,research,lifescience,medical to milder forms of bipolar illness. In the prospective studies, nonhospitalized mood episodes were assessed, but evidence in support of kindling was not consistently attained. Some of this research suggests that kindling phenomena may characterize a subgroup of patients with bipolar disorder, perhaps with more severe illness. A recent, yet to be published, study from the National Institute of Mental Health (NIMH) Depression Collaborative research program51 also found no evidence to support kindling-like phenomena, and however instead reported that poor outcome was associated with polyphasic mood episodes, rather than monophasic mood episodes. Thus, patients whose mood episodes cycle directly between depression and mania had a worse outcome than those who experience a single episode followed by a period of euthymia. The investigators in the latter study suggest that amount of time ill is a better criterion for poor outcome than number of episodes and shortening of episode cycles, as suggested by the kindling hypothesis.