Beck: Understanding of Depression Ready for New Paradigm

Are there genetic and neurobiological correlates for the cognitive theory of depression?

Aaron Beck, M.D., famed founder of cognitive-behavioral therapy and the cognitive theory of depression, believes that there may be and that there are now avenues of research available for finding out.

In a wide-ranging retrospective in the July 15 AJP in Advance, Beck says the time has come to seek out a genetic and neurophysiological basis for the cognitive theory of depression.

“The accumulation of studies of the psychological and biological aspects of depression has reached a critical mass warranting a new synthesis,” he writes. “The findings of relationships among the diverse genetic, neurophysiological, environmental, and cognitive aspects of the vulnerability to and development of depression call for future studies integrating these findings into a comprehensible formulation.”

As one example of a promising line of research, Beck suggests that recent work on the interaction between environmental stressors and genetic susceptibility in the development of depression appears to provide a gene-by-environment-by-neurobiological pathway for the development of the negative beliefs and the tendency toward depressive rumination characteristic of depression.

For instance, he cites the landmark research by Avshalom Caspi, Ph.D., reported in the July 18, 2003, Science. Caspi found that individuals having the short variant of the 5-HTTLPR (serotonin transporter) gene experienced higher levels of depression and suicidality following a recent life stressor.

Building on this, Beck says new research indicates that negative cognitive processing and negative cognitions are associated with the presence of the 5-HTTLPR short allele. For instance, in a study comparing nondepressed 7-year-old children with and without the short allele who were shown sad movie clips or asked to imagine a sad experience, the children homozygous for the short allele showed greater negative processing on a self-referential encoding task than did children with other genotypes.

That report, “Early-Emerging Cognitive Vulnerability to Depression and the Serotonin Transporter Promoter Region Polymorphism,” appeared in the April Journal of Affective Disorders.

“Thus, the accumulating evidence suggests the genetic predisposition to depression is associated with biases in the processing of information,” Beck writes.

Furthermore, Beck links this evidence to findings from functional brain imaging to suggest a neurophysiological link to cognition. Noting that multiple findings have tied amygdala hyperactivity to depression, Beck states that recent research has tied the 5-HTTLPR variant to hyperactivity in the amygdala.

“Hyperreactivity of the amygdala in the short 5-HTTLPR variant carriers is associated with increased sensitivity to negative stimuli and leads to negative bias in the processing or interpretation of emotional stimuli,” Beck writes. “Since the amygdala is involved in the evaluation and storage of emotionally charged events, its hyperreactivity to negative stimuli in predisposed individuals would appear to represent a neurophysiological correlate of cognitive bias.”

It is an ambitious agenda that Beck lays out, and he proposes a“ deconstruction” of depression in which genetic or neurophysiological processes are parallel to the developmental stages in depression, as represented in the cognitive theory.

First he recounts the central tenets of that theory: early adverse events foster negative attitudes and biases about the self, which are integrated into the cognitive organization in the form of “schemas” about the self (“I am unlovable, I am inadequate, I am worthless”); when the schemas are activated by an event or series of events, they skew the information processing system, which then directs attentional resources to negative stimuli and translates a specific experience into a distorted negative interpretation.

This results in the systematic negative bias at the core of depression.

Next Beck proposes a hypothetical genetic and neurophysiological pathway for each of the components of the theory starting with genetic vulnerability.

“The 5-HTTLPR polymorphism leads to excessive reactivity of the amygdala,” Beck suggests. “The heightened limbic reactivity to emotionally significant events triggers deployment of increased attentional resources to such events, manifested by negative attentional bias and recall. The selective focus on the negative aspects of experience results in the familiar cognitive distortions such as exaggeration, personalization, and overgeneralization and, consequently, the formation of dysfunctional attitudes regarding personal adequacy, acceptability, and worth. Frequent reiterations of negative interpretations shape the content of the cognitive schemas (unlovable, inadequate, worthless).

“Concurrently, the negative interpretations of experience have an impact on the hypothalamic-pituitary-adrenal axis and set in motion [a] cycle involving the over-reactive serotonergic system and consequently lead to depression.”

Simple, right? Not really—the research required to elucidate this picture comprehensively would require successive “waves” of studies over the lifetimes of large groups of children.

“A series of waves, starting in early childhood, should examine the variables associated with the polymorphism: assessments of information processing biases, negative cognitions, and dysfunctional attitudes following negative mood inductions,” Beck proposes. “These findings would then be compared with studies of brain activity to determine their associations with the limbic system as well as prefrontal cingulate and other regions. The early studies would determine whether automatic cognitive processing precedes the development of negative cognitions and dysfunctional attitudes. Another wave could examine diary records of daily dysfunctional cognitions in response to stressful situations and relate these to cortisol responses to specific stimuli situations. Overall, these assessments over a long time span would integrate findings from neuroimaging and neuroendocrine responses to stressors with cognitive responses to daily stressful activities as well as to major life events.”

That's a long-term and complicated agenda, but Beck ends on a hopeful note.“ I have reason to hope that future research will perhaps provide a new paradigm, which for the first time can integrate findings from psychological and biological studies to build a new understanding of depression,” he writes.

Beck's article, “The Evolution of the Cognitive Model of Depression and Its Neurobiological Correlates” is posted at<http://ajp.psychiatryonline.org/pap.dtl> and will appear in the print edition of the journal in August. An abstract of“ Early-Emerging Cognitive Vulnerability to Depression and the Serotonin Transporter Promoter Region Polymorphism” is posted at<www.sciencedirect.com/science/journal/01650327>. An abstract of the Caspi study, “Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene,” is posted at<www.sciencemag.org/cgi/content/abstract/301/5631/386>.▪