For a variety of reasons, I've been thinking a lot about depression  recently, not only about peoples' experiences with it (including my own) but also about how to make sense of it from a neurobiological perspective. A variety of conversations, including a recent one in a senior seminar course in neural and behavioral science , has significantly added to my thoughts, helped to crystallize some of them, and suggested some intriguing directions for further exploration.
These days, most people think of depression in terms of a contemporary pharmacology-based "medical model ", the core of which is the idea that depression is an "illness" resulting from "chemical imbalances". From this perspective, the actual feelings and experiences that depressed individuals have are of relatively little interest, either therapeutically or in terms of trying to better understand depression, and the principle task is to find ways to "correct" the underlying disturbed pharmacological pattern.
My own guess has been and continues to be that while there are certainly pharmacological correlates to depression, the condition does not at all reduce to those, and that a fuller understanding of both depression and ways to treat it depends fundamentally on paying more attention to individual feelings and experiences, to observations made and reported "from the inside ". This intuition reflects, in part, experiences with treating depression pharmacologically that have been gained since new pharmacological treatements became available. Those observations seem quite clearly to be saying that that some pharmacological treatments can be helpful for some people at some times but no pharmcological agent is effective for all people at all times. And that, in turn, is consistent with my intuitions as a biologist and neurobiologist. Given the complexity of the brain and its variation from one person to another, it is inconceivable to me that there is any fixed relation between pharmacological profile and behavioral state in individuals, much less that the same relation holds across different human populations. Equally importantly, one's mental state is a function not only of pharmacological and external variables but also of things going on inside one, one's internal feelings and experiences . The latter are not only not fully determined by pharmacological and external variables but in turn influence both pharmacological and external variables.
In short, depression (like any other mental state) refects a rich, complex, and bidirectional interplay of influences, no one of which is determinative in any individual. Pharmacological agents can of course influence these interactions but should be expected to be, at best, a quite coarse tool for doing so. One might sometimes improve the function of a high performance engine by changing the oil that bathes it, but that's a distinctly limited approach to the problem of sustaining effective function of the engine, to say nothing of enhancing it. And this is, of course, even more the case with brains, which not only reflect a still richer and more complex bidirectional web of influences but also vary quite significantly form individual to individual.
So, where does one go from here? One certainly does not want to deny the worth of pharmacological manipulations, either for therapy or as a tool for better understanding depression  (among other mental conditions). At the same time, there is clearly, in both respects, a need to move beyond the purely pharmacological approach to something both more subtle and more individualized. In this regard, there is more than a mild irony, indeed a potentially tragic irony, in the tendency in medical circles (and in the health care industry generally) to regard pharmacological manipulation not as an adjunct to but instead as a replacement for earlier approaches to making sense of and treating depression (see Of Two Minds: An Anthropologist Looks at American Psychiatry  and Have You Ever Been in Psychotherapy, Doctor? ).
The irony is that a body of more subtle and individualized approaches, various forms of "talk therapy", existed prior to the development of contemporary pharmacological approaches, and the tragedy is that we may be losing them as a body of expertise and a source of continuing insights precisely when the need for them, on both counts, is becoming most evident. Rather than contending over the relative merits of pharmacological approaches and talk therapy, there is a clear need to begin trying to understand how they two relate to one another, how they can best be used in complementary way, and what their joint efficacy is telling us about what depression actually is.
There are in fact some already some encouraging movement along these lines. A particular form of talk therapy, cognitive behavioral therapy, has begun to be recognized within the medical community as a procedure whose effectiveness may in some cases may be comparable to pharmacotherapy. Still more significantly, it is becoming clearer that talk therapies, like pharmacotherapies, produce observable effects on the brain and that in some respects the effects on the brain are similar . Neurobiologists, who presume that changes in behavior always correspond to changes in the brain, are not surprised by this, but it clearly serves as important reassurance to others who have doubted that talk therapy could be a way of producing observable changes in the brain.
Even more interestingly, there are suggestions that while talk therapy (cognitive behavioral therapy in this case) and pharmacotherapy produce similar changes in some areas of the brain, they do so by influencing in different ways other areas of the brain.  The therapeutic effects of pharmacotherapy seem to reflect a primary action on more primitive areas of the brain, those responsible for unconscious activities, while the therapeutic effects of cognitive behavioral therapy (at least) seem to depend instead on primary action on parts of the brain involved in our awareness of ourselves and our surrounding, those involved in conscious activities.
This in turn offers a possible opening for further thinking about the relations between pharmacotherapy and talk therapy in depression, both conceptually and therapeutically. As a neurobiologist, I've been struck by the need in a variety of contexts to acknowledge that there are distinguishable unconscious and conscious (or story telling) processes going on in the brain, and that the brain function in general involves a continuing dynamic exchange or negotiation between the two.  My own experiences with depression have long seemed to me to make sense in terms of a breakdown in this dynamic exchange, particularly if one accepts that feelings and intuitions represent signals from the unconscious that contribute to the vividness and functionality of our conscious experiences. In lieu of those, the conscious feels helpless, bereft, empty, and has great difficulty marshalling the resources for even simple tasks. Conversely, the conscious feels genuinely unable to alter or even significantly influence one's own feelings. The upshot is a sense of profound discomfort (sometimes associated with anxiety and agitation, other times with profound lethargy) that is difficult to localize and next to impossible to describe (see William Styron's Darkness Visible).
There is an intriguing parallel to the experience of depression in that of motion sickness. In this case, a profound but difficult to localize discomfort that frequently begins with agitation and resolves into lethargy results from a substantial conflict in the brain between two sets of signals that relate to one's perception of stability or motion relative to one's surroundings. One set of signals originates in sensory pathways, from the eyes, the inner ear, and other sensory endings in the body. The other set originates within the nervous system itself, and consists of "corollary discharge" or "efference copy"signals sent by parts of the nervous system causing output to the muscles to other parts of the nervous system for use in intepreting inputs. When a comparison of the two sets of signals yields no sign of conflict (I'm sitting and my sensory input shows no motion of me relative to the environment); I'm walking and the sensory input I'm getting shows motion of me relative to the environment), all is well. When there is a severe mismatch of the two sets of signals (I'm sitting but my sensory input suggests substantial motion of me relative to my surroundings; I'm walking but my sensory input implies no motion), there is discomfort and in the end a desire to lie down and go to sleep.
The possible parallels between motion sickness and depression may well be worth exploring futher in a number of respects (the effectiveness of drug treatments versus other kinds of therapy, the variation in individuals, etc) but, for the moment, one additional feature of motion sickness seems worth noting. With no significant mismatch between the two relevant sets of signals, one is unaware of the ongoing comparison between the two. With very significant mismatch, one feels very substantial discomfort. Between these two extremes, there is a continuous spectrum of possible outcomes of the comparison, with an increasing degree of conflict as one goes from one to the other. This intermediate spectrum of conflicts is being continually used by the nervous system to fine-tune motor outputs, interpretation of sensory inputs, and the comparison between them itself. The upshot is an ongoing process of mutual adaptation that gives the brain an ability to function effectively over a wide and somewhat unpredictably varying set of circumstances.
It is tempting to think of depression in the same terms, as a breakdown in a normally continual exchange between the unconscious and the conscious, one in which each adapts to the other in ways that facilitate adaptive function over a wide and somewhat unpredictable set of circumstance. The sets of signals being compared could in this case be reports from the unconscious of its current state, observed as feelings and intuitions, and the conscious story of oneself, who one feels/believes onself to be. Under normal circumstances, there only small conflicts between the two sets of signals, and those are used to make small adjustments both of the unconscious and of the story to bring them into correspondence. When however the conflict is great enough to preclude easy adjustments of one or the other, the exchange breaks down and serious depression results.
Such a story of depression as an unconscious/conscious dissocation provides a straightforward explanation of why both pharmacotherapy and talk therapy can be therapeutically effective: one can bring back into correspondence the unconscious and the conscious by action on either, with pharmacotherapy perhaps acting primarily on unconscious processes and talk therapy on conscious ones. Indeed, cognitive behavioral emphasizes the distinction between unconscious and conscious processes and is directed specificaly at the latter. Patients are encouraged and helped to distinguish their feelings and intuitions from themselves (their conscious "story"), to acknowledge that their unconscious processes may be defective, and hence to create a new story about themselves in which they can recognize and avoid acting out of the defective unconscious processes.
An increasing recognition of the role of "story" in therapeutic practice, and of its observable impacts on brain function, is a positive movement that could facilitate a needed greater recognition of the complexity of the brain, of the role of internal experiences in its function, and hence of the quite significant variation from individual. At the same time, cognitive behavioral therapy doesn't, it seems to me, go quite far enough down this road. There are rich bodies of expertise in older talk therapy traditions, including the psychoanalytic , that one might hope to somehow bring on board in a new and still broader approach. And there remains in the cognitive behavioral therapy approach more than a little of the "medical model" flavor: patients are encouraged to use their own story telling capabilities but to do so in the context of an agreed upon "defect" in their unconscious processing.
A broader approch to talk therapy might retain, with both cognitive therapy and various other existing forms of psychotherapy, a central recognition of the distinction between unconscious and conscious processes and of the contributions both make to one's behavior and experiences without granting primacy to either (Writing Descartes  and Making the Unconscious Conscious and Vice Versa ). The task is neither to make the unconscious conscious (as is sometimes asserted for psychoanalysis) nor to rely on the conscious to notice and correct defects in the unconscious, but rather simply to facilitate an ongoing process of negotiation between the two. From this perspective, conflict is not a problem to be resolved but rather the source of continuing growth and development, and becomes a problem only when it comes great enough to stall that process. The task of the therapist is simply to encourge and facilitate that process, using whatever tools achieve that end in any given case, tools that would be expected to vary enormously from case to case given the enormous variety of ways the unconscious and conscious can conceivably come into serious conflict.
Among other desireable features, such an approach would necessarily and appropriately acknowledge the need to treat depression in ways that are more subtle and more individualized. Indeed, such an approach would acknowledge that depression is not necessarily in all cases best regarded as an "illness" or defect in the individual that needs to be "repaired." An alternate perspective is that depression is an extreme form of a quite normal and adaptive feature of brain organization. And that at least sometimes, even in the extreme form, it continues to serve the function of reconciling conflicts between the unconscious and the conscious. "Psychological unease can generate creative work and the rebirth after depression brings a new love affair with life ... Don't beat yourself up about being depressed, in most cases it wil run its course provided you take yourself out of the situation that caused it ... Sometimes its not easy to escape but that's the fault of society, not the fault of depression" (Paul Keedwell, quoted in Is Depression Good for You? ). Maybe sometimes the best treatment for depression is to simply provide a supportive environment for the brain while it works out its own individual resolution?
Are drugs useful for depression? Of course, sometimes. Is talk therapy useful? Yes of course, sometimes. Is there more to depression than a chemical imbalance? Almost always, perhaps always. Are one's own feelings and experiences significant in depression? Yes, always. Is depression useful? It can be, if the circumstances are right. Does depression make sense as an unconscious/conscious dissociation? Perhaps. Is there more to learn about depression? From depression? Unquestionably.
Depression's Evolutionary Roots  - 25 August 2009
Mind over meds  - 19 April 2010