Many psychotherapists pay little attention to evolving knowledge from neuroscience and psychiatric genomics. They may argue, for example, that there is little about what is happening in the dorsolateral prefrontal cortex, insula, or amygdala of people in states of health or disease that sheds much light on the practice of psychotherapy. In the area of psychiatric genomics, though, there is interesting and relatively new information worthy of psychotherapists’ attention.
THE BIOPSYCHOSOCIAL MODEL IS BETTER SUPPORTED THAN THE BIOMEDICAL MODEL
In the late 1990s, Francis Collins, now head of the National Institutes of Health, but then head of the National Human Genome Research Institute, confidently predicted to the field of medicine that once the human genome was decoded, we would unearth the genetic causes of medical and psychiatric disorders and witness the development of many targeted biological treatments.1 This notion, effectively that we would learn how genes=disease in the human genome, has not proven to be true, particularly for mental disorders, in light of the data that have emerged subsequent to the decoding of the human genome in 2003.
Multiple large Genome Wide Association Studies (GWAS) have revealed that there are many single nucleotide polymorphisms associated with specific mental disorders—hundreds of single nucleotide polymorphisms found in GWAS studies of schizophrenia and dozens for depression—while the same single nucleotide polymorphisms are often associated with multiple disorders, like autism, attention deficit disorder, bipolar disorder, and schizophrenia.2–4 The notion that “genes=disease” has given way to the recognition that what actually matters are “gene-by-environment” (G×E) interactions—that is, there is a complex interplay between what is encoded in a person’s genome and such environmental factors as trauma or early adverse experiences, and that it is these G×E interactions that lead to states of disease—and to resilience.5 I propose that “gene-by-environment” interaction is really just another way of saying “biopsychosocial,” with biological factors, like genes, as well as psychological and social contextual experiences, such as early adversity, working together to cause—and cure—mental disease. One way the process of gene-by-environment interaction appears to work is by the so-called epigenetic phenomenon of DNA methylation.
WHAT IS DNA METHYLATION?
Most of us understand that the genes in our chromosomes are clusters of DNA or deoxyribonucleic acid. We also probably recall that there is much more DNA in any given cell than is expressed (or active) at any moment. Just a portion of our DNA is on the workbench, if you will, at any one time. A useful way to understand this is to think of DNA as being like our personal cell phones. All of us who own a given cell phone model start with pretty much the same apps, which in this metaphor are comparable to genes. There are many more apps installed on a cell phone at purchase than we run at any one time. Our DNA is similar. It has lots of apps in the form of gene systems, more than we use on the genetic workbench at any one time.
The DNA app—a system of genes—in use at any one time is like the cell phone app currently in use. An important mechanism for changing gene system apps is DNA methylation—a process in which a cytosine to guanine bond is formed in the presence of a methyl group—hence DNA “methylation.” A methylated segment of DNA becomes tightly coiled and inactivated—taken off line, if you will. Methylated DNA remains inactivated until and unless it is demethylated in some way, once again making the DNA app available. Hence, methylation and demethylation are switches that turn DNA apps, and, on a larger scale, entire gene systems, off and on.6
This process is what makes monozygotic twins become different over time. Although they start with exactly the same DNA, over time their different life experiences lead to different patterns of DNA methylation, and to the differences we see in their phenotypic expression over the years. What do we know about what causes methylation and demethylation of DNA?
TRAUMA AND DNA METHYLATION
There is a good deal of evidence that early adverse experiences like trauma can lead to mental and medical disorders.7,8 There is also evidence that DNA methylation occurs in response to trauma or other early adverse experience in animal models.6,9 In humans, DNA methylation appears to be a relevant factor in mental disorders. For example, DNA is differentially methylated in key regions of DNA associated with schizophrenia,10 while different genetic loci are associated with depression in women with and without histories of adversity.11 There is also preliminary evidence that, in patients with posttraumatic stress disorder, DNA methylation of some single nucleotide polymorphisms may predict posttraumatic stress disorder treatment outcome, independent of whether treatment is with drugs or psychotherapy.12
Animal models help us learn about DNA methylation and demethylation. For example, newborn macaque monkeys that have been separated from their mothers develop massive behavioral change and large-scale methylation of their DNA in response to this trauma.6 The methylated DNA is found in every cell in their bodies—brain cells, blood cells, liver cells, ova, and sperm. In fact, that there is methylated DNA in egg and sperm likely explains the intergenerational transmission of trauma that psychotherapists have been aware of for over 50 years.
It is what reverses DNA methylation that is of particular interest to psychotherapists. In a lecture at the 2015 annual meeting of the American Psychiatric Association, Szyf13 reported that such DNA demethylation (reversal of methylation) occurred in macaque monkeys after periods of quiet reflection in their cages when cued by the scent of the lost mother. Such periods of quiet reflection in the presence of a reminder of the lost mother sound a lot like mourning and grief work.
The pharmaceutical industry will undoubtedly search for blockbuster drugs that demethylate DNA in methylated gene systems impacted by trauma, but we are wise to hold gene-by-environment biopsychosocial processes in mind and think beyond drugs and the profit motive in considering ways to induce DNA demethylation.
DNA METHYLATION, MOURNING, AND PSYCHOTHERAPY
The mathematician George Box taught us that “all models are wrong; some are useful.”14 One of my first supervisors as a fellow training in psychoanalysis at Austen Riggs, the late Martin Cooperman, offered me one of these wrong but useful models that speaks directly to the value for psychotherapists of what we are learning from translational research with monkeys about DNA methylation and demethylation. Cooperman taught that, “All psychopathology is loss; all psychotherapy is mourning.”
Over the years I have held Cooperman’s oversimplified and undoubtedly wrong model in mind, and I have found it extraordinarily useful. Again and again, my work as a therapist has involved forming trusting relationships with patients and then helping them face grief and loss, often related to trauma, during the periods of quiet and intense reflection in their sessions, and cued by thoughts and memories, sometimes by dreams, related to the lost object or trauma. I believe that we therapists are partners in periods of quiet reflection that, among other important processes, likely help our patients mourn in ways that, on a molecular level, demethylate gene systems impacted by trauma and loss.
It is useful for psychotherapists to hold in mind contemporary learning from psychiatric genomics for its heuristic value in offering useful models for thinking about our work. Knowing a bit about this area of emerging science also helps us build bridges with biologically focused clinicians, allowing us to join them in thinking about what causes and what treats mental disorders using shared understanding of what it means to be human.
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2. Hyde CL, Nagle MW, Tian C, et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat Genet. 2016;48:1031–1036.
3. Sekar A, Biala AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–183.
4. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–1379.
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9. Provencal N, Suderman MJ, Guillemin C, et al. The signature of maternal rearing in the methylome in rhesus macacque prefrontal cortex and T cells. J Neurosci. 2012;32:15626–15642.
10. Montano C, Taub MA, Jaffe A, et al. Association of DNA methylation
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11. Peterson RE, Cai N, Dahl AW, et al. Molecular genetic analysis subdivided by adversity exposure suggests etiologic heterogeneity in major depression. Am J Psychiatry. 2018;175:545–554.
12. Pape JC, Carrillo-Roa T, Rothbaum BO, et al. DNA methylation
levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder. Clin Epigenetics. 2018;10:136.
13. Szyf M. Epigenetic processes mediating the impact of social environments on mental health and disease. Frontiers of Science Lecture Series, presented at the annual meeting of the American Psychiatric Association, May 18, 2015, Toronto, CA.
14. Box GEP. Science and statistics. J Am Stat Assoc. 1976;71:791–799.