Clinical pleomorphism of major depression as a challenge to the study of its pathophysiology

There are many studies showing that, as a group, major depressive disorder is associated with abnormalities in neurotransmitter systems such as serotonin, norepinephrine, dopamine, GABA and glutamate, as well as in neurotrophic factors which are in turn affected by hyper-responsive stress response systems such as the hypothalamic-pituitary-adrenal axis and altered cytokine function. Finally, there are alterations in circadian rhythms and sleep architecture which may be the consequence of these abnormalities or contribute to the risk or alter the course of major depression. It has long been puzzling how to reconcile research approaches looking at a single biologic explanatory model with the heterogeneity of the clinical picture of major depression. It would seem that this pleomorphic picture must be reflected by an equal variety in the pathophysiology. An examination of the DSM-IV criteria for a major depressive episode indicates there are over 1000 combinations of features that allow one to make that diagnosis. Furthermore, researchers point to the interindividual variability in score profile across the items of scales like the Hamilton Depression Rating Scale (HDRS). But this view only tells part of the story. We reported that there was no quantitative relationship within patients between episodes of major depression 1. This was true whether one examined the overall severity of successive episodes (as in the HDRS total score), or factors derived from a factor analysis looking at relatively independent domains of psychopathology, or even when one examined individual item scores. The key point here is that clinical presentation seems to vary about as much within patients in successive episodes, as between patients. The implications of this phenomenon were recognized by Eugen Bleuler in his landmark book on schizophrenia 2. He linked catatonia, paranoid schizophrenia, hebephrenia and what he called a defect state because he observed all of these in different combinations appearing in the same patient over time. In other words, even though these clinical pictures looked very different, they seemed to be part of a single illness since they were manifested by the same patient. If we consider that illnesses such as major depressive disorder or schizophrenia result from genetic causes and reported childhood adversity, including famine and physical or sexual abuse, and these environmental effects occur early in life, then the biological predisposition to illness should be largely set in an individual by early adolescence. If we presume that this biological substrate is fairly stable, then it is difficult to explain why there is such a variation in clinical picture within individuals. One possibility is that each episode alters the brain biology due to some sort of scaring or sensitization. Epigenetic effects may be a mechanism for enduring changes. But then one would predict a similar set of steps in terms of the evolution of the illness over time (as seen in schizophrenia with the evolution towards more negative symptoms and fewer positive symptoms). In major depression, the changes in clinical picture do not seem to follow a simple pattern, except perhaps for a longer duration of episodes. Brain imaging studies offer some clue in this respect and raise further questions. We have reported that the severity of different clinical domains of major depression, as defined by factors derived from either the HDRS or the Beck Depression Inventory (BDI), correlate with relative resting regional brain glucose uptake as measured by [18F]-FDG positron emission tomography (PET) 3. The degree to which these factor scores are correlated with each other is highly related to the degree to which the brain regions overlap for different factors. Each factor is related to a partly independent brain region 3. Clinical heterogeneity is reflected in a corresponding variety in relative resting regional brain activity in major depression. Not surprisingly, successful treatment with antidepressants or psychotherapy can alter this pattern towards that seen in healthy volunteers, and induced sadness in healthy volunteers can reproduce some of the changes seen in major depression 4. This provides a biological basis for variation in clinical picture, but not a causal explanation or mechanism. There are more stable biologic abnormalities that are present during episodes of major depression and between episodes. The best example is the abnormality in the serotonin system, which has been shown in terms of return of depression during remission after acute tryptophan depletion from the brain, the blunted prolactin response to the indirect serotonin releasing drug fenfluramine during an episode and between episodes, and the higher 5-HT1A receptor binding on PET imaging in depressed and remitted drug-free patients. To further study the clinical and biological heterogeneity between patients, one would recommend a focus on regional brain variation as revealed by the PET FDG studies and then seeking a cause for that variation in terms of serotonin, neorepinephrine and dopamine inputs and GABA and glutamatergic target neuron function.