Genes and Mental Illness - Four False Assumptions of Contemporary Psychiatry Part Three
Continuing our look at the first of 4 false assumptions of contemporary psychiatry, the one that assumes genes will prove to be the cause of mental illness, let’s focus on the game changing work of Caspi’s group first published in 2003—one of the most cited papers of this century.
Caspi studied variations in the promoter gene for the serotonin transporter. This gene controls manufacture of the proteins of the serotonin “pump” affected by selective serotonin reuptake inhibitor antidepressant drugs (SSRIs), and therefore likely important in the genetics of depression. If you recall basic genetics, there may be different “alleles” for a gene—as in the one for brown eyes and the one for blue eyes. In the case of the SERT promoter gene, there are 2 different alleles, one long (l) and one short (s). A person may be heterozygous with a long and a short allele (ls), or homozygous for the short (ss) or long (ll) alleles for the SERT promoter gene. Interested in epigenetics, i.e., the link between environment and genes, Caspi looked at the impact of early adverse experiences, like childhood deprivation, loss, abuse or neglect, on the risk of depression later in life as a function of allelic variation in the SERT promoter gene. He found that those with early adverse experiences who had homozygous short alleles (ss) were more likely to develop depression than those homozygous for the long alleles (ll). This finding offers a glimpse into how genes and environment work together, while raising the question of whether homozygous short alleles constitute a genetic vulnerability for depression.
It gets even more interesting when you look at the rest of the data. In the presence of early adversity, homozygous short alleles increase the risk of depression compared to homozygous long alleles, suggesting we have found evidence of genetic “vulnerability,” BUT IN THE ABSENCE OF EARLY ADVERSITY, those with homozygous short alleles had the lowest risk of later depression—a lower risk than those with homozygous long alleles or heterozygous long and short alleles. This is the game changer, the paradigm shifting bit of new information. Suddenly, what initially looked like a sign of genetic “vulnerability” proves to be a sign of genetic “plasticity,” as Belsky has called it. Those with homozygous short alleles appear to have an increased risk of depression in response to an environment with early adversity. However, this same genetic endowment confers resistance to depression in the absence of early adversity. In fact, others, like Eley, have found that positive environmental experiences confer a decreased risk of depression in those with homozygous short alleles (which raises an interesting question about whether this is one way that psychotherapy or participation in a therapeutic community confers its benefits). If genes work principally by conferring different degrees of plasticity rather than vulnerability to environmental influence, then the current search for genetic vulnerability is a search for a holy grail that can never be found.
Now, let me be the first to point out that Caspi’s and Karg’s and Belsky’s and Eley’s findings in this domain account for only a small amount of the variance in determining whether someone will develop depression, but this is no surprise. As already noted in a previous posting, even large genome wide association studies have failed to find evidence of genetic vulnerability for depression. It seems to me a reasonable clinician or researcher who saw this data would want to think in an entirely new way about how genes and environment work together—and think about treatment in a way that pays much more attention to the crucial beneficial effects of environmental factors, like relationships and communities.