Loose ends of psychiatric research.

Reading psychiatric research literature of the last several decades frequently gives the impression of fragmentation, where old research topics are abandoned for newer ones without proper follow-up that would place the existing data into a coherent structure. Such perspective is increasingly relevant though, as medical research draws more and more on methods that allow exploratory analyses of large amounts of data without having to specify a priori hypotheses. As in most medical research, methods of genome-wide association analyses, gene expression and proteomic profiling studies, and voxel-based morphometry and functional brain imaging studies have been prominent tools in psychiatry. They frequently end up with barely significant findings, and the validity of their results is often claimed post hoc on biological or pathophysiological grounds. Sometimes such claims are rather tenuous (e.g., rel evance of a genetic polymorphism based on the fact that the specific gene is also expressed in the brain). It is well established that genetic findings in complex traits are hard to validate and to show conclusively how they contribute to disease susceptibility. Brain imaging findings are often based on small and clinically heterogeneous samples with similar consequences for interpretation of any findings. Thus, it is even more imperative that new psychiatric findings be put into a pathophysiological framework built on earlier results. In psych iatry, such knowledge is fairly limited, putting the field at a disadvantage compared with other areas of medicine. For instance, Alzheimer disease, diabetes mellitus, inflammatory bowel disease, multiple sclerosis or Parkinson disease are all complex traits, typically less heritable than major psychiatric disorders, but their genetic research has advanced faster, benefiting from prior knowledge of their pathology and pathophysiology. Although the mechanisms of these disorders are far from completely understood, the available information has helped to select candidate genes and/or interpret the genetic findings. Slow progress of research can be attributed to various causes. They are not exclusive to, but are often more promin ent in psychiatry. First, research moves along trends that tend to leave behind inconclusive and partial results that are not easy to fit together. Yet, we believe that many of the now abandoned studies reported real findings in real patients, and if interpreted in proper context they could contribute to the modern understanding of psychiatric illness. For instance, electrolyte changes have been postulated as a possible pathophysiological mechanism of bipolar disorder since the 1960s, and shifts in ion balance have been documented repeatedly as being associated with transitions in the clinical course (from mania to euthymia to depression). With the wider application of lithium (Li), the hypothesis became even more compelling. Abnormalities of membrane ion transport have been proposed as the mechanism of bipolar disorder, and some authors have suggested that abnormalities of Li membrane transport could be used as a diagnostic test. Few years later, this research was abandoned, perhaps prematurely, following reports of unreliable laboratory methods, poor intraindividual reproducibility of some of the measures and unsatisfactory correlation of per ipheral (red blood cell) and brain transport mechanism. And yet, similar investigations in hypertension have generated intriguing findings potentially relevant for psychiatry. Patients with bipolar disorder are known to have increased rates of hypertension and higher cardiovascular mortality, and reproducible abnormalities of Li–sodium countertransport are among well-established biological markers of essential hypertension. A number of examples just in the area of mood disorders can be found in studies of sleep deprivation effects on depression, cholinergic REM sleep induction or once trendy neuroendocrinological research. The dexamethasone suppression test (DST) has been one of the most studied abnormalities in mood disorders and was considered a candidate for a diagnostic test of depression. Yet, hundreds of papers later, we can only acknowledge that the hypothalamo– pituitary– adrenal (HPA) axis dysregulation is associated with several serious psychiatric disorders, but the actual mechanisms and their relation to other neurobiological findings are just barely being uncovered. More recently, the neuroprotective effect of Li has attracted much attention. It is well supported by animal and human studies that Li increases expression of multiple molec ules known to be neuroprotective and that it does increase hippocampal volume and concentration of N-acetylaspartate in