In the Sept. 25th issue of Science is a review article entitled, “Genetics and genomics of psychiatric disease” by Daniel Geschwind and Jonathan Flint, who announce in the abstract that “advances place us on the threshold of a new frontier in the pathophysiological understanding, diagnosis, and treatment of psychiatric disease.” Unfortunately, I have been hearing that for 25 years.
When Prozac was introduced in 1988, my patients started telling me that mental illness is a “chemical imbalance” and “all in the genes.” The success of Prozac enabled brain biologists to seize center stage, denouncing Freudian concepts as the idols of a pagan religion. After the neurochemistry of mental illness was found to be a hopeless jungle of complexity, impossible to discriminate between cause, compensation, and effect, investigators turned to genes as potential “anchors” in the shifting seas of this chemical soup. Back in the 1950’s identical twin studies had demonstrated that, similar to all behavioral traits, mental illness has a sizable genetic component.
At issue in this paper for me is the authors’ messianic attitude that the only way to understand cause of mental illnesses such as the major depressions, bipolar disorder, and schizophrenia is through the genes. They open the article by stating that “Genetic findings are set to illuminate the causes…of psychiatric conditions, some of which, until recently, were purported to have a non-biologic etiology.” Here they cite an article written by Bruno Bettelheim in 1972 about autism. That’s over forty years ago when autism was a backwater. No one has “purported” (a lawyer’s word) that autism does not have a substantial biological component since its incidence has been uncovered (&/or increased) in the last twenty years. In fact the paper points out that autism (Geschwind’s specialty) is the only psychiatric disorder in which significant genes of large effect have been found. Mental illnesses, like other complex disorders, are caused by many genes of small effect. Furthermore, they state, “In the majority of cases, loci identified through GWASs (genome-wide association studies) lie in regulatory regions of the genome and do not unequivocally implicate a specific gene.”
The sheer complexity facing these researchers can be ascertained by this excerpt:
Additionally, there is an inherent tension between the study of individual genes and the emerging genetic architecture of psychiatric illness, which implicates potentially thousands of genes in each disorder. If psychiatric disorders are a collection of rare conditions, then detailed individual investigation is the most direct route forward. The evidence supports this hypothesis at least in part for ASD (autism) and other childhood-onset disorders, in which we now know that the effects of different rare major–effect-size alleles account for some of the phenotypic complexity. Yet there is remarkably little evidence that this is true for SCZ (schizophrenia), BPD (bipolar disorder), major depression, substance abuse, and the anxiety disorders. The apparent specificity of drug action in some of these conditions might be interpreted to imply shared mechanisms among responders. Yet one would not assume shared etiologies among patients with infectious or rheumatologic diseases, whose fevers symptomatically respond to aspirin. The existence of only a few central switches that determine vulnerability to illness is challenged by the extreme polygenicity [many genes of small effect] and apparent genetic heterogeneity in these disorders. We need to understand in an unbiased manner whether there is a convergence of these multiple complex genetic factors on a relatively constrained set of biochemical pathways.
It is not my intention to denigrate the efforts of these scientists to understand mental illnesses from the “bottom-up”. They offer the eventual hope for targeted treatments for these dreaded conditions, to which I have devoted my career. My concern is that they continue to discount that a “top-down” understanding could supplement and assist their understanding.
My “functional” understanding is that the vulnerability for mental illness is similar to our vulnerability to lower back-and-lower limb joint pathology: the genetic susceptibility to this endemic problem stems from the evolutionary fact that the advantages of upright posture simply out-weighed it. I have explained in this blog that our Homo sapiens species is characterized by the evolution of intense motivations for “self-display,” which were superimposed upon six million years of evolution of collective, group-oriented motivations. As a species we have accrued the benefits of the internal integration of “two minds,” which has afforded the benefits of strengthened bonds in ever larger groups, and led to the mental capacities of reflective self-awareness and thought plus complex linguistic syntax. If I am right, just as we would not find pathological mutations that cause lower limb pathology, so too will we not find pathological mutations that cause mental illnesses (autism might be an exception). Like our back-knee-and-hip problems, mental illness is a “side-effect,” and the mentally ill should be respected for paying the price for our extraordinary capacities.
I would certainly support the sentiment expressed by Geschwind and Flint that,”…the field is at an appropriate juncture to consider when it would be reasonable to stop looking for genes [for mental illness] and focus entirely on studying their function.