It frequently comes as quite a shock when people learn that depression is now the most expensive condition facing Western societies, when you put together the cost of treatment with the cost of lost productivity (including the devastating cost of total disability for an unfortunate few who are knocked off the road completely by depression). This means depression is actually costing more money than Alzheimer’s disease (#3 on the list), more money than cancer (#4), and more money than even heart disease and stroke (#2). How is this possible? Isn’t depression simply a ‘chemical imbalance’ that can be neatly chemically rectified? We’ve never had more antidepressant drugs on the market than we have right now, so what’s gone wrong?
Well, in all honesty, almost everything, in terms of how we’re approaching the problem. First of all, our fundamental concept of depression is profoundly distorted, the treatment climate is subsequently distorted by these more-wrong-more-than-right ideas, and subsequently, we’re getting rather poor results – and in that sense, the poor results should not be a surprise. A complete rethinking of the problem is called for, and with a virtually clean sheet of paper so to speak. It all starts with our severely distorted concept of what depression really might be, as some kind of “chemical imbalance,” a meme that has led to a standard of care in which psychotherapy and other psychosocial and lifestyle interventions have virtually fallen off the treatment map, in the US anyway, and where the standard of care revolves around so-called first-line antidepressants, and if a single agent fails, then polypharmacy, including increasing use of neuroleptics, drugs with a host of serious and even dangerous metabolic side effects.
The notion of a “chemical imbalance” harks back to the early days of the ‘psychopharmacology revolution’ when a seductive biological reductionism took hold in psychiatry, under the aegis of the assumption that commonplace conditions such as depression, bipolar disorder and schizophrenia would soon all be reduced into a handful of simple neurotransmitter imbalances. That has not proven to be the case, not just in relationship to depression, but in relationship to virtually every other condition in the psychiatric nosology and DSM. Indeed, in relationship to depression, virtually every neurochemical signaling system that’s been examined in any detail appears somehow altered – that includes not just the famous amine systems (serotonin, norepinephrine and dopamine) that we can manipulate, but the amino acid signaling systems of glutamate and GABA, several neuropeptides including two distinct opioid systems (mu and kappa), substance P (originally discovered in relationship to pain), oxytocin (recently gaining attention for its role in regulating social bonds and trust), the peptide at the head of the stress cascade, corticotropin releasing factor (CRF), and, as if this imposing list were not enough complexity, even cytokine systems, traditionally viewed as immune signals. What’s going on with this complex system of modulatory controls in depression?
Depression is associated with a general down-regulation of amine systems, a down regulation of GABA, an upregulation of glutamate and Kappa opioids, while prosocial peptides such as oxytocin and mu opioids are down-regulated, while the stress axis appears stuck on ‘high’, and not being normalized by negative feedback from cortisol, in part due to the influence of pro-inflammatory cytokines. Indeed, as conveyed by the above summary, the entire system of neuromodulatory controls appears to pivot around an axis that we call ‘depression’, where the locus of control for this process looks quite diffuse and highly distributed, as a whole bunch of neurochemical signaling systems influence one another and reverberate in very complex ways. There is evidence for example that increased kappa opioid signaling is shutting down dopamine (and with it, our motivation and reward-seeking), while the stress axis upregulation is promoting not just a conscious dysphoria but also driving the upregulated kappa opioid signals, while declining mu opioids and oxytocin may contribute potently to the stress axis upregulation. This suggests not any version of a linear feedforward cascade or ‘falling dominoes’ but rather a complex recursion in which a bunch of interacting factors determine entry into as well as exit from a depressive trajectory. Additionally, traditional antidepressants (excepting stimulants and amphetamines which affect dopamine) only modulate two amine systems – serotonin and norepinephrine – that have at best rather indirect effects on the stress axis, virtually no interaction with other important prosocial peptide systems (such as mu opioids and oxytocin), and not much effect on inflammatory signals, a restricted locus of action that may explain their frankly minimal efficacy. Indeed, a dirty secret that has been systematically obscured by big Pharma is that traditional antidepressant drugs do not separate from placebo in mild to moderate depression, and only separate from placebo in moderate and worse depressions, probably because the placebo mechanism (‘positive expectancy’ in other words) is starting to fall apart, likely due to the depression itself. This picture of minimal efficacy and no separation from placebo only emerges if one combines both the published and more positive trials with the suppressed, unpublished and negative trials – something achieved in several recent meta-analyses. So we now have a standard of care in this country for mild to moderate depression – placing people on first-line antidepressants and doing little else – that in fact does not have an empirical basis. How in the world could this have happened? Well, it’s due to the corrupting influence of powerful commercial interests and the manner in which big Pharma has far too much influence on drug research trials in this country, including, until recently, the right to suppress negative trials. It looks more and more like having big Pharma run its own drug research trials to determine efficacy and safety is a bit like having the fox research the chickens.
In simplest terms, traditional mainline antidepressants simply don’t appear to get very far into the heart of this depressive shutdown process (orchestrated by interactions between stress cascades, upregulated kappa opioids, declining mu opioids and oxytocin, upregulated pro-inflammatory cytokines, and perhaps other shifts in many other regulatory neuropeptides that have not yet been characterized). Since we have had a massive transition to a standard of care in which mainline antidepressants are often times the only treatment depressed patients ever received under the widespread influence of this meme of ‘chemical imbalance’, is it a surprise therefore that the treatment climate is currently not terribly successful?
The other problem with a simple ‘chemical imbalance’ meme is that it never came close to explaining the ubiquitous nature of depression (virtually everyone has had at least a mild version of depression), or the fact that every mammal that’s been looked at and studied appears to show a version of depression neurobiologically identical to ours, even if they lack our cognition, and its attendant depressive rumination. So, in that sense, depression appears to be a built-in vulnerability in mammalian social brain affective endowment, and not simply an ‘illness’. The human illness may reflect the disinhibition or hypertrophy of this built-in mammalian brain mechanism. But why and how did Nature build in this mechanism through the evolutionary process? Seems a bit cruel doesn’t it? We believe that a depressive mechanism was selected because a time-limited, circumscribed version of depression may have been adaptive, first of all around terminating the dangers of protracted separation distress in infant mammals, and then later in development, terminating the dangers of interminable dominance conflicts in older animals – two scenarios with significant potential for fatal outcomes. In both those instances, continuing to be highly affectively aroused would increase the likelihood of fatal consequences. There are times when it might be a good idea to just give up and shutdown, especially in the context of a small infant creature that has just lost its primary source of metabolic supply (the ‘parental units’) and where continued squawking (AKA separation distress calls) is likely to both exhaust the small creature, and also serve as a beacon for predators. In any case the idea that depression is an evolutionarily conserved mechanism, and that it functions to terminate separation distress fits beautifully with how losses and other forms of social defeat (such as getting fired) are the most commonplace triggers for a depressive episode. In other words, depression is not a ‘chemical imbalance’, it’s a conserved shutdown mechanism elicited by certain prototype stressors, and perhaps serving as protection from our beating our head against the same wall over and over again, and forcing us to go back and re-think, retool, and recalibrate. If this is true, it should have profound implications for our treatment landscape, suggesting that depression treatment needs to address losses and other precipitating stressors (instead of ignoring them), reduce commonplace social isolation, reduce pro-inflammatory lifestyle factors instead of ignoring them, and in general, reengage and reconnect depressed individuals.
Dr. Douglas Watt was trained in psychology and neuropsychology at Harvard College and Boston College, completing his PhD studies in 1985. His dissertation addressed commonalities and differences in the presentation of severe character pathology in hospitalized inpatients. He did his postdoctoral internship at Human Resource Institute, specializing in projective psychological and neurocognitive assessment of hospitalized inpatients. Over 30 years of clinical practice, he has served as Director of Clinical Psychology/Clinical Neuropsychology in two Boston teaching hospitals. He was on the faculty of the Boston University School of Medicine for 15 years. He was a faculty member at the Boston Graduate School of Psychoanalysis and Institute for the Study of Violence for four years, where he has taught doctoral level courses on affective neuroscience and its implications. He is a prolific scientific author and educator. His current clinical and research interests center on Alzheimer’s disease, its relationship to delirium, and how basic lifestyle factors contribute to or prevent it.