Rather than looking at the biological basis for depression, it may be more useful to look at the patient's worldview and how that may have primed them for depression. Examining events that took place in the patient's past lead to a solution to their current depression.
I was called to the emergency room late one evening to evaluate a 50-year-old man who had taken an overdose of his antidepressant medications mirtazapine (Remeron) and trazodone (Desyrel). "Ed," who had diabetes, also claimed to have injected 170 units of short-acting, regular insulin (his daily dose was 15 units). He called his estranged wife and told her what he had done. She immediately phoned a man who lived in the house where her husband rented a room, and he dialed 911.
Ed was lying on a gurney, hooked up to intravenous lines delivering electrolytes and dextrose. His affect was flat: his face had no expression, his voice no modulation. He looked and sounded depressed and described himself as feeling very depressed. "I don't want to live" was his answer when I asked why he took the overdose.
The 15 mirtazapine and 25 trazodone tablets Ed took were not life-threatening. Without treatment, 170 units of insulin would kill someone with glucose initially in the normal range (60 mg/dL to 110 mg/dL). Ed told me he was taking the mirtazapine and trazodone as prescribed, but had stopped taking insulin several months earlier. Ironically, the resulting hyperglycemia had saved him. (His glucose level was 136 mg/dL in the ambulance, 90 mg/dL in the ER and 270 mg/dL after the first infusion of dextrose, given to counteract the insulin overdose.) Six hours after Ed reported taking the overdose he was lethargic, but knew who he was, where he was and the date; he gave adequate, if minimal, answers to all the questions I asked.
Five years earlier, after working there for 20 years, Ed had lost his job as vice president of operations for a company that made glass products. "I saw it coming," he told me. "They got someone to work cheaper." Ed had a degree in business from a prestigious university. Since being laid off, his life had been what he called a "slow slide downhill." He had held several jobs for short periods, but hadn't worked for two years. "I've lost everything," he reported without emotion; his losses included the respect of his family. He was living in a rented room, had no money in the bank and was nearing the end of his unemployment insurance.
Ed's appetite was good, and his weight had stayed constant, but he had not eaten in two days because he could not afford to buy food. He was sleeping well. (The normal appetite and sleep are unusual for someone reputedly so depressed.) Ed had been depressed for eight years before losing his job and saw "many doctors" during that time. Both parents, now deceased, were diagnosed with depression.
Eight months earlier, Ed had taken an overdose of 100 acetaminophen (Tylenol) tablets, intending, he said, to die. He did not go for medical treatment. Later, he told his estranged wife about the overdose. At her insistence, he signed himself into a psychiatric hospital, where he stayed for 30 days and received electroconvulsive therapy. Ed was convinced his depression was due to a "chemical imbalance" and that he could do nothing about it, despite being told by doctors at the hospital that this was not the case. He insisted that he had not benefited from his contact with any mental health care clinician. Mirtazapine and trazodone had not helped him; neither had ECT. Patients who believe their depression is biologically determined often experience at least a placebo effect with these interventions, but Ed did not.
Ed gave the distinct impression of being helpless and hopeless. His self-esteem was zero. When I asked if he could imagine what it would take to get beyond his depression, he told me with conviction that he did not know. He didn't seem bothered by his lack of an agenda for getting out of the hole he had dug for himself, or as he thought of it, the hole his "chemical imbalance" had dug for him. He appeared totally passive with respect to his situation. "I'm not ready to get another job," he assured me.
Ed denied having delusions or hallucinations, the distortions of perception that those with severe depression sometimes experience. He had never been paranoid. His DSM-IV diagnosis was depressive disorder, recurrent, severe, without psychotic features. Fifteen years earlier, Ed had used cocaine for one year, but not since, and he had not tried any other street drugs. He never abused alcohol.
By phone, Ed's estranged wife confirmed the main points of his story, along with my suspicion that Ed had done little to help himself since losing his job. She had encouraged him to apply for Social Security disability for his depression, an indication that both of them considered his condition permanent. Ed readily agreed to a voluntary admission to a psychiatric hospital, his second in eight months. Before leaving the ER, I challenged his belief that a chemical imbalance made any effort to overcome his depression futile. He stuck to his guns and again insisted he could do nothing to help himself.
How can we understand Ed's situation? The following explanation, which fits so many of the depressed patients I have seen, comes from the philosopher Jean-Paul Sartre, who is also recognized for his contributions to existential psychoanalysis (Sartre, 1962). Sartre believed that individuals who become depressed after facing a negative experience--typically a loss, defeat or rejection--trick themselves into believing that they are incapable of going beyond the loss. It is as if one road had closed down, and the disappointed person self-indulgently refuses to allow another road to open up. To Sartre, this was considered an "attitude of excuse," and an act of self-deception.
Through what Sartre called a "magical transformation," the depressed person's formerly instrumental, euthymic world loses its differentiation and simultaneously its appeal (Fell, 1965; Sartre, 1948). The instrumental world is highly differentiated, which is to say a person who lives there values some of its offerings more than others and selectively responds to its invitations. Differentiating one's world goes hand-in-hand with developing one's self. As the German existential psychiatrist Karl Jaspers explained in his General Psychopathology (1997):
Increased differentiation brings increased clarity and awareness. Undefined intuitions and feelings give place to clear, definite ideas. From an undifferentiated state of innocence emerge the innumerable contradictions and conflicts of our psychic life.
Clearly, differentiation is a prerequisite for psychic health.
An instrumental, differentiated world is a world of cause and effect: projects are started, goals are set, risks are taken. One is willing to be patient, to tolerate setbacks, to overcome obstacles, to defer gratification. In the instrumental world, individuals act as if what they do--how they choose to use the freedom that allows them to construct a world--will influence their fate.
Ultimately, depression is a rejection of this kind of world. The depressed person acts as if the requirements for those who live in an instrumental, differentiated (and thus euthymic) world no longer apply. As the Dutch psychiatrist J. H. van den Berg, M.D., (1972) put it, the depressed person lives "a different existence."
Clearly, Ed had de-differentiated the world he formerly lived in and through. His pathological reconstruction had a flattened terrain, so that what he now saw was uninteresting and unworthy of his attention. His flattened affect was part of that flatly constructed world. Ed's depression was not in him or in his de-differentiated, flattened, valueless world; but it was between him and that world and was ultimately the relation he had to it. Ed had tricked himself into believing that he could not overcome the disappointment of losing his job five years earlier (and no doubt other disappointments that came before and after that loss). He had no hope that his life could be different and saw no future for himself. I was surprised that he did not show any signs of anger, which is common in depression, during our interview. Those feelings, too, may have been ground down and homogenized in the de-differentiation of his world. Ed was in despair.
Ed's choice of a de-differentiated world was made in the context of his "facticity," what Sartre saw as everything a person receives in the throw of the dice that precedes the gift of human freedom: who his parents were, what genes they passed on, the era he was born into, his social position, his sexual orientation and so forth. (David L. Ulin  was capturing this dialectic when he wrote, "[It] is both the blessing and the curse of humanity, to exist between free will and history.") Usually, while evaluating a patient in the ER, I can get a good sense of what these factors are. But Ed had little to say. His answers were strictly factual, short and crisp, with no spontaneous elaboration. He had no insight into his situation and did not seem to want any. Nonetheless, it may be possible to say something about the genetic component of Ed's facticity, since both parents were treated for depression, and he had type I diabetes. Depression is more common in patients whose parents have been depressed, although no one can yet distinguish what is passed on through the genes here from what is learned at home. Depression is also common in patients with diabetes, and a direct physiological link between endocrine and mood disorders has been proposed (Anderson et al., 2001).
Many people lose their jobs and respond instrumentally. Ed may well have been primed for the passive response he made by one or more components of his facticity. His development--how he responded to the challenges presented to him through the life cycle--inevitably figured in as well. There is empirical evidence that, to some degree, life experience is imprinted on the brain's neural substrate, most likely in part through changes in gene expression and the subsequent synthesis of receptor proteins. This imprinting may influence the neural tone of some brain circuits, including those that underlie mood.
I suspect that Ed was rather narcissistic. His body was the shell of a formerly good-looking man. I got the impression that he was once used to having things go his way, and he had a strong sense of entitlement. His de-differentiated world, now tuned solely into himself, may have been tuned there all along. Not once in the interview did he give any indication that his wife or three children had been inconvenienced by the way he was living. During ER evaluations, patients usually express concern about the others they have invariably, if unintentionally, hurt because of their mental illness. Not Ed.
Narcissists overly identify with some ideal scenario of what they feel their lives should be and the role others should play in that scenario. These individuals take disappointment and loss hard. Their response to negative experience accounts for some of the most virulent pathology associated with this personality trait. I suspect that, after losing his job and being confronted with the shattered image of what he thought his world should be, the structure of Ed's personality predisposed him to de-differentiate that world.
The psychiatrist Viktor Frankl, M.D., Ph.D., a prisoner of the Nazis during World War II, wrote in Man's Search for Meaning (1984) about the role choice played in the fate of camp inmates. Some gave up and died quickly. Others, constructing for themselves a different kind of world from the fragments of their tragedy, survived, overcoming the injustice that had been done to them. Influenced by Sartre's ideas, Frankl showed that the meaning one gives to negative experience determines how one comes through it. The severity of Ed's depression followed from the number of components of the instrumental world he had de-differentiated, and from how tightly he held to these transformed constructs. The de-differentiated world he created held him down, leading to his depression. That world was very likely made of pathological "self-schemas," patterns of aberrant thinking, feeling and behavior that cause those who live this way extreme emotional pain and poison their relations with others (Markus, 1977; Markus et al., 1990). In quasi-psychodynamic language, instead of authentically facing, suffering through and eventually overcoming the pain of his loss by dealing with it in an existential domain, Ed defended against the pain in a psychopathological domain, and became depressed.
There are significant points of convergence between Sartre's theory of de-differentiation and the cognitive theory of depression that connects depression to negative thinking (Beck, 1972; Beck et al., 1987). The negative thoughts that are challenged by cognitive therapists, in what is often a highly effective approach to treating depression, can be seen as the cognitive structural elements of a depressed person's de-differentiated world. These negative thoughts, which are intrinsically pathological and ineluctably lead to depression, need to be distinguished from the negative thoughts that merely make us sad, and leave differentiation intact. This kind of cognition is universal, can be part of one's authentic experience, and is compatible with an instrumental construction of the world.
There's an old saying: Where we stand depends on where we sit. This, it seems to me, is another way of stating the notion that we construct our own world. Some self-disclosure may help to explain why I see depression as I do. Although I have had major disappointments and been betrayed--and suffered mightily as a result--I have never had the symptoms of clinical depression. My explanation for this is that I suffered on the existential level, mostly using mature defenses and avoiding immature defenses as much as possible, until I was able to overcome the negative experience and get on with things (Vaillant, 2000). I recognized the temptation to de-differentiate what I was feeling, but refused to make this inauthentic choice, and mostly continue to refuse it in the face of new negative experience. In other words, I choose not to become depressed. I suspect that my development, which was not compromised by any major traumas, as well as the fact that no one in my immediate family has ever experienced depression (apparently, I didn't "get" it through the genes, and I didn't "learn" it at home), helped make my choice to stay in the instrumental mode easier.
A Brain Correlative of De-Differentiation
The stress inherent in the lived pathological self-schemas of those who, like my patient Ed, experience major depression almost certainly has a brain correlative. The de-differentiation posited here seems too radical a deformation of consciousness and too great a consequent stressor to the body not to be biologically imprinted. The well-studied hypothalamic-pituitary-adrenal (HPA) axis very likely links mind and brain in all emotional experience. One can wonder if those people who de-differentiate their world in this pathological way most strongly and globally are the ones who develop treatment-resistant depression, requiring long courses of high-dose antidepressants or electroconvulsive therapy. Changes in brain structure and function may act as a ballast to perpetuate the pathological self-schemas that are coincident with de-differentiation, exerting their influence through the HPA axis and other routes.
Just how much of a "brain disease," or "chemical imbalance," Ed had remains a challenging--and for the most part unanswered--question. It is possible that depression's chosen pathological self-schemas are themselves the essential structural components of depression (Muller, 2003). It is not known if the changes seen in brain scans of depressed persons are causal, collateral or epiphenomenal. If the changes are not specific to depression, they do not define it. What has been observed in these pictures may even be due to a general stress response.
It has been suggested that antidepressants act indirectly as stimulants to "brighten" mood, rather than by correcting a brain chemical imbalance that "causes" depression (Glenmullen, 2000), which is the prevailing view now in biopsychiatry. Before tricyclic antidepressants came on the market in the 1950s, depressed patients were successfully treated with prescription doses of amphetamine and cocaine. Since no one knows how antidepressants work, it seems prudent to keep the stimulant hypothesis in the differential until the mechanism of this drug action is understood. (I suspect that antidepressants first "boost" serotonin and norepinephrine brain circuits, then after several weeks, augment reward-modulated limbic dopamine circuits, thereby "lifting" mood.)
In spite of data accumulated from many empirical studies, what we think of as the brain-mind gap has not been closed. The fact is, we do not yet understand how the contents of consciousness are related to brain structure and function (McHugh and Slavney, 1998).
Adolf Meyer, M.D., professor of psychiatry at Johns Hopkins Medical School from 1910 to 1941, approached mental illness from the perspective of what he called psychobiology, which he saw as a dialectical (two-way) interaction between brain and mind (Lidz, 1993, 1966). At first glance, this may seem to be what biopsychiatry is doing now, but it is not: biopsychiatry sees mental illness for the most part as a (one-way) biological malfunction of brain structure and function. During his years at Johns Hopkins, Meyer cast a long shadow, training many of that era's most influential psychiatrists. But his psychobiology lost out first to psychoanalysis, then to biopsychiatry. Although his name is not widely known in psychiatry now, Meyer's approach has been assimilated (often without attribution) by many of us who do clinical work and try to parse out the meaning of what we do. George Engel, M.D.'s, oft-cited biopsychosocial approach to understanding and treating psychopathology is largely a restatement of Meyerian principles (Davidson and Strauss, 1995; Engel, 1980; McHugh and Slavney, 1998). We would do well to return Meyer's descriptive designation psychobiology to the lexicon of psychiatric dialogue. Engel's term biopsychosocial is an unpleasant and unwieldy mouthful of a word that lacks the cachet to nail the idea that we need to approach mind and body without dichotomy.
The process of de-differentiation that Sartre posits as the essence of depression has the potential to become the "psycho" component of a renewed psychobiological effort to understand the ultimate meaning and structure of depression. This project would be greatly helped by tapping into the collective wisdom of the existential-phenomenological school of psychiatry, a European tradition that is not well-known in North America. The main players here include Frankl; van den Berg; Ludwig Binswanger, M.D.; Medard Boss, M.D.; Erwin Straus, M.D.; Karl Jaspers, M.D.; and R.D. Laing, M.D. (May et al., 1958). Most of these clinical theorists were influenced by Sartre's ontology, that branch of philosophy that studies the structure of being (Luijpen, 1960).
Can De-Differentiation Be Empirically Validated?
A major step forward here would be to identify and characterize the pathological self-schemas that make up the depressed state. Severely depressed people could be asked to write detailed descriptions of how they think, feel and act. These texts could then be analyzed to see if certain structural elements recur in their descriptions and if these elements seem to be the necessary (and possibly even sufficient) psychological constituents and determinants of depression. The writer could later be questioned about elements in the text that seem to require amplification. A crucial part of this research would be to identify the self-deception involved when a person goes from a pre-depression instrumental stance toward the world to the de-differentiated stance of the depressed state. (This transition may well turn out to include some variation on the "I can't do it"--i.e., remain in the instrumental mode--theme.) Primary data of this kind, extracted directly from human experience, would provide a map of the surfaces, contours and textures of the de-differentiated world of the depressed person. Control data could be extracted from descriptions of those who faced negative experiences but stayed in the instrumental mode, and did not become depressed (where, intuitively, one would expect not to find pathological self-schemas).
The technique for doing this kind of textural analysis has been worked out in detail and used to elucidate the meaning and structure of many phenomena (Giorgi, 1985, 1970). Hundreds of psychology doctoral dissertations have been based on data generated in this way (Smith, 2002). The empirical method of intuiting essences used here derives from the phenomenology of the German philosopher Edmund Husserl (1859-1938). This method could supply the heuristic program missing in the approaches of Meyer and Engel, the principal limitation of their work.
A recent New Yorker profile of Massachusetts Institute of Technology linguistics professor Noam Chomsky, Ph.D., gives this gloss of language "deep structure," a concept that made Chomsky an academic icon (MacFarquhar, 2003) (italics added):
For half a century, social scientists and philosophers had told themselves that the mind was murky and amorphous, impossible to study in a rigorous way, so it was better to ignore it. Chomsky declared that they were wrong: the mind was a beautiful system, and its construction was visible in language; he who solved language's puzzle would win the greatest prize of all, knowledge of the structure of thought.
Perhaps with the empirical study I am proposing here what seems murky and amorphous about human emotion could be interrogated and persuaded to disclose what Chomsky would call "the structure of [depressed] thought," along with the feeling and behavior that go with it. Such a study implies a question that we cannot as yet answer: To what extent does our consciousness, and the freedom that marks it, have the power to construct and sustain the thinking, feeling and behavior we call depression? For now, biopsychiatry is ceding this capability solely to a brain "chemical imbalance."
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