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Depression as a Cancer of the Self

Research-based treatments provide hope for treating this dreaded disease.

The World Health Organization ranks depression as the second greatest cause of disability worldwide. (1) This reflects both the psychological and physiological manifestations of depression, which afflicts more than 20 percent of the world’s population. While 35 million Americans take antidepressants, only 60 percent respond. Disturbingly, many depressed patients receive no treatment at all. (2) In addition to causing great anguish and disrupting interpersonal relationships and work, depression’s physiologic changes promote premature coronary artery disease, stroke, diabetes, and osteoporosis. (3-12) Consequently, the lifespan of patients with depressive illness is shortened by 7-10 years. (2)

One of the two forms of depressive illness, melancholic depression, is associated with insomnia, often early morning awakening, loss of appetite, and depressed mood, which is most severe in the morning. The cardinal manifestations of melancholic depression intrude upon many features that define our humanity. Melancholic depression contradicts the term depression in that it is often a state of hyperarousal and anxiety, especially about the self. Melancholia is characterized by a malignant transformation characterized by the anguish of feeling utterly worthless. A second malignant transformation consists of losing the capacity to anticipate or experience pleasure and the incapacity to feel that life has meaning. While patients with melancholic depression are often bombarded by negatively charged emotional memories of helplessness and failure, they cannot remember ever feeling well. For these reasons, I call melancholic depression a cancer of the self. (2,13,14,15,17)

I had previously written that depression reflects a stress system that has run awry. (13-17) In melancholic depression, the stress system seems distorted and chronically activated, as indicated by their increased secretion of stress hormones (17), sympathetic nervous system activation (18-20), and insomnia. (2,13-17) To provide another concrete example, during stress, there is only a modest decrement in the capacity to experience pleasure to prevent distraction so that stressed individuals are not so demoralized that they are impeded from effectively seeking to counteract the threats to which they are exposed. During melancholic depression, there is a much more extreme loss of the capacity to experience pleasure that significantly interferes with function and profoundly impoverishes the quality of life. (2,17)

One of the key sites of neuronal pathology in melancholic depression is the subgenual prefrontal cortex, which loses as much as 40 percent of its volume and much of its function. (21,22) When working properly, this site promotes self-esteem, restrains anxiety, and enhances the capacity of the pleasure and reward center to generate the experience of pleasure. (2,13-17) Thus, its impairment contributes significantly to feelings of worthlessness, anxiety, loss of the capacity to experience pleasure, and loss of the capacity to adequately restrain hormone secretion and the sympathetic nervous system. (23) Thus, melancholic individuals have stress hormone levels that are greatly increased. (18-20) During a normal stress response, such as that occurring during delivering a speech, healthy individuals experience mild inflammation (17), which occurs to anticipate and aid a potential injury incurred during dangerous situations; increased blood clotting as a stay against possible hemorrhage (4); and increased levels of blood sugar to provide the necessary fuel for the stressed brain. (2,6,12,13) Depressed patients experience clinically significant inflammation, pathological increases in blood clotting, and deleterious increases in plasma glucose concentrations. (8,9)

The second major form of depression is atypical depression, which is no less of a cancer of the self than melancholic depression. It seems the antithesis of melancholic depression and presents as an inactivation of the stress response. (13-17) Instead of being bombarded by negatively charged emotional memories, patients with atypical depression often feel walled off from their emotional memories, themselves, their loved ones, and their friends, and can feel lonely and empty. (2, 13-17) We have shown that patients with atypical depression have decreased levels of stress hormones. (24) And though they lose the capacity to anticipate or experience pleasure, they further differ from melancholic patients by experiencing chronic fatigue, loss of motivation, increased sleep, and increased appetite. Their depression is more severe in the morning than in the evenings. Individuals with atypical depression fail to respond to some drugs that are effective in melancholia. (2, 13-17)

Rene Spitz made seminal observations about infants in orphanages who were left alone. After an initial period of crying until they were attended, they subsequently withdrew and ceased crying when they were left alone or hungry for long periods. It was as if the trauma of their early deprivation led to a shut-down of their stress response and affective existence to protect them from enormous distress. (25) Studies in non-human primates showed that infants removed from their mothers and raised by peers manifested a similar behavioral withdrawal in association with low cortisol levels. (26) These may represent very severe forms of atypical depression.

Depression is a neurodegenerative disease affecting sites such as the subgenual prefrontal cortex as well as the hippocampus. (2,13,14) This is partially mediated by stress, inflammation, and the neurotransmitter glutamate. (2,17) Unfortunately, depression is a far worse illness than we had previously suspected. It is not only associated with widespread damage and destruction of brain cells that encode identity, self-esteem, and other key aspects of our humanity (2,17) but also by substantial inflammation in the brain and throughout the body (3). Neurons in depressed individuals fail to properly connect (26-28) and there is a marked reduction in the births of new neurons that promote the capacity to deal with complex, shifting environmental stressors. (2,17) Moreover, synapses, or the spaces that bridge nerve cells and through which they communicate, are damaged and decreased in number (28-30), and neuronal pathways atrophy and malfunction. There is good news, however. Recent research has led to the development of 30 new rapid-acting compounds that seem more effective than the antidepressants of the 20th century (17). They are profoundly neuroprotective and partially promote the restoration of cells lost by neurodegeneration (17). Others activate the brain’s reward center, promote the birth of new nerve cells, repair synapses, and restore damaged nerve pathways (17). Thus, there is great hope for future treatments.


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