20-25 Since patients with diminished insight deny the presence of certain symptoms they actually possess, lack of insight is obviously one of those subjective factors which could affect accurate diagnostic assessment of mood and psychotic disorders. Directions for genetic research Turning to genetics, the ideal neurobiological hypothesis must explain two fundamental features of mood disorders: genetic vulnerability

and episodic recurrence. In Inhibitors,research,lifescience,medical recent reviews of the genetic literature,26-28 there is a consensus that findings regarding chromosomes 5, 11, and X are inconclusive; however, there arc possible linkages on chromosome 1829,30 and chromosome 21q.31,32 In spite of these intriguing findings

regarding possible single loci, most of the genetic epidemiology studies suggest a polygenic disorder. Of relevance to genetic research is the kindling paradigm, which Inhibitors,research,lifescience,medical posits an analogy between the episodic nature of mood disorders and the phenomena of kindling and sensitization.33 While a direct link between the physiological process of kindling and clinical recurrence has not been definitively established, the hypothesis possesses the advantage of encompassing key aspects of MEK inhibitor drugs bipolar illness: the onset of earlyepisodes are preceded by major stress whereas later episodes are not; the severity of untreated mood episodes worsens over time; and Inhibitors,research,lifescience,medical the interval between episodes decreases over time.34 Now how might this have a bearing on genetic research? Compared Inhibitors,research,lifescience,medical to older animals, younger ones require a lower level of electrical or chemical stimulation to initiate and sustain limbic kindled seizures.35 Clinical genetic data suggest 15 % to 20 % of children of a parent with bipolar disorder may develop the disorder. It is possible that, in the future, genetic markers Inhibitors,research,lifescience,medical with predictive validities near 80 % would allow testing of the efficacy of antikindling agents in genetically vulnerable children before their first bipolar episode. Once beyond the high-risk period, one might be able to evaluate whether treatment could be withdrawn without the illness having ever expressed itself.

Outcome Parvulin Traditionally, the outcome of patients with bipolar disorder has been reported to be intermediate between schizophrenia and nonpsychotic unipolar major depressive disorder. Recent naturalistic outcome data from several research centers suggest rather poor outcome in bipolar disorder, even when treated.36-38 However, in evaluating the meaning of this, we must recall that tertiary care research centers include a selection bias because they treat more severely ill patients. The old adage in medicine that the longer a successful treatment is available, the more difficult it becomes to show it still works, certainly applies to lithium, where research in practice settings continues to support its effectiveness.