Science and the Future of Psychiatry

— di Huda Akil, PhD & Stanley J. Watson, MD, PhD —

Archives Gen. of Psychiatry - Vol. 57 No. 1 - January 2000

If humanity is lucky, the evolution of our knowledge of the living world will result in the elaboration of more perfect scientific eyes to probe the nature of the human brain and to understand the complexities of the human mind.

This seems to be the best path to truly helping individuals who are battling psychiatric illnesses and to actually preventing many brain-related disorders.

For such accomplishments to take place, the trajectory of our science has to change, to move from its unrelenting reductionism to a serious attempt at integrating knowledge that spans from the structure of the gene to the expression of complex cognition.

The tension between the biomedical and the psychotherapeutic approaches in psychiatry needs to be eliminated and transformed into a fully integrated approach that is mindful of the biological, emotional, cognitive, and social complexity of each individual.

Arch Gen Psychiatry. 2000;57:86-87 The history of the living world can be summarized as an elaboration of ever more perfect eyes, within a cosmos in which there is always something more to be seen.-Pierre Teihlard de Chardin, The Phenomenon of Man There is little doubt that the explosion of knowledge in the life sciences at the end of the millennium will yield heretofore unimagined tools for the increased understanding we need.

The challenge will no longer reside in the availability of fundamental information, but in its thoughtful integration.

The avalanche of data on the sequence and variation of the human genome may be staggering, but understanding how such variation might relate to behavior, personality traits, or psychiatric illness will truly challenge our scientific skills.

It will require all our intelligence in framing questions, recognizing profiles and patterns, and establishing criteria for determining cause and effect relationships.

While our colleagues in other fields of biomedical research will also have to address the issues related to complex genetics and gene-environment interactions, we in brain research will face this problem most acutely.

This is because we deal with a complex organ whose very function is to learn and change through experience. All along, we will need to be mindful of the impressive plasticity of the brain not only during development but throughout life.

The genes, while they set the parameters of the program, do not by any means fully determine the outcome. At the same time, it is critical to understand the parameters that lead to the dysregulation of brain function, as diseases of this organ alter our very identity and our place in the world.

It will likely be necessary to elaborate an intermediate level of knowledge that can serve as a stepping-stone between specific genetic information about an individual and the behavior of that person.

We term this a neuronal phenotype, which consists of understanding patterns of gene expression and function within the brain, presumably as the critical mediators between the original genetic endowment and the expression of behavioral patterns.

These neuronal phenotypes represent unique patterns of gene expression, in the context of known brain circuits, that are the end result of interactions between the genetic endowment of the individual and the impact of various developmental and experiential events on the brain.

Thus, identical twins with identical genetic endowments may have differing neuronal phenotypes owing to their unique experiences, leading to the differential likelihood of suffering from a psychiatric disorder.

It is only by having a much fuller understanding of the neuronal phenotypes that we will be able to perceive the critical differences that lead to the expression of an illness or its avoidance. But the concept of neuronal phenotype can be broadened to be more dynamic and inclusive.

Thus, while these phenotypes can be described in terms of patterns and magnitude of gene expression in a particular circuit at rest (eg, how much corticotropin-releasing hormone is expressed in the amygdala and glucocorticoid receptors in the hippocampus), they can also be described in terms of neuronal activity in response to a challenge (eg, how much dopamine is released in the prefrontal cortex vs the nucleus accumbens during a particular task), as well as the impact of an event on subsequent neuronal events (eg, how much induction of immediate early genes or of other signaling events takes place in a circuit because of exposure to a stimulus and for how long).

Optimally, we would become much more sophisticated at obtaining whole profiles of activity in the context of these neuronal phenotypes, coordinating information about starting levels of activity and reactions to input over neuronal space and time.

Thus, our more perfect scientific eyes would be able to fully probe the human brain in action, at various phases of life and under different conditions, and to understand the functional dynamics of this organ.

This understanding would go far beyond the knowledge we now obtain from neuroimaging tools to simultaneously relate the global regional activities that we currently measure to the activities of the specific genes, proteins, and circuits being brought into play at any given instant.

In this idealized world, we would literally be able to follow a perception, a thought, or a learning process through its key molecular and anatomical stages and see its repercussions at subsequent time points.

It is likely that such tools will simultaneously lead us to revisit some fundamental assumptions and reveal misconceptions about the nature of psychiatric disorders. For example, they may lead us to the notion that many mood disorders have a stronger cognitive component than previously anticipated.

They may allow us to detect preverbal or nonverbal variables that nevertheless play a key role in social and emotional responsiveness. Even more likely, they will lead us to reorganize our most fundamental views of brain function, moving us away from the old Cartesian categories to entirely new functional neuronal entities.

Why would such a level of understanding at the molecular and neurobiological level be useful in helping people? At the broadest level, it would begin to translate the real implications of the fact that psychiatric illnesses are the result of complex genetics.

In the last few years, we have come to realize that most psychiatric disorders are not due to a single gene but result from gene-gene interactions, involve gene-environment interactions, and exhibit a great deal of heterogeneity, such that the same disorder can be the result of different combinations of genetic predispositions.

While this makes our work in understanding the genetics of psychiatric illnesses much more arduous, it also gives our field and our patients much hope. It says that biology is not destiny, and vulnerabilities if identified and understood need not turn into psychiatric disorders.

But to truly understand how complex genetics come into play in leading to psychiatric disorders, we need to watch various genetic programs in action during development, maturation, and aging, following various stressors with or without the illness before and after treatment with either pharmacological agents or psychotherapy.

We need to grasp how certain events at critical times alter the course of development. We need to comprehend how experience in the adult brain, including social interactions, modify particular circuits in reversible and irreversible ways.

We need to measure the impact of the illness itself on the expressions of specific genes in the specific individual in the context of the unique vulnerabilities of that brain. Only then would we have sufficient and systematic information to attempt to stem or reverse the critical neurobiological events that may spell the difference between normal emotionality and full-blown depression or between interesting thoughts and florid psychosis.

The day may come, sooner than we might like, when a newborn would receive full information about his or her genetic structure, including various polymorphisms that may make him or her more vulnerable to depression, autism, or Alzheimer disease.

This would be a huge burden on the individual unless we could couple this information with knowledge of what one can do to help prevent the expression of these disorders. In the case of severe disorders, such as autism, what may be needed is early and fairly aggressive intervention using a range of tools from particular drugs to gene therapy.

But in the case of numerous brain disorders, including many of the mood disorders and even possibly some of the age-related disorders, much could be accomplished by understanding the role of environmental modulation on these processes.

In some cases, the changes may be nutritional; in others, they may well be behavioral. Social interactions, and therefore talking therapies, can change brain structure and function just as drugs can. A thoughtful combination of approaches would need to be elaborated and would require our combined efforts at the scientific and ethical levels.

Huge efforts in education would be necessary to help people implement these strategies for themselves, their children, or their students. Careful public policy decisions would need to be made to ensure that this knowledge remains private and is not abused.

But the greatest gain that psychiatry could offer, through a more enlightened scientific basis and a greater wisdom in its application, is something that humanity has been seeking throughout the ages-self-knowledge coupled with greater acceptance of ourselves and of others, and a way of dealing with this great gift of self-consciousness that can carry with it the burden of the deepest human suffering.

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