DEPRESSION

By Douglas F. Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.

In the conventional view, depression is just an illness caused by a chemical imbalance, commonly treated with SSRIs or SNRIs that are both safe and effective.  All four of these popular notions may be more wrong than right, and they all contribute to a basic obfuscation of depression’s core biological mechanisms widespread in our medical industrial complex.  These popular misconceptions also hide a fundamental failure of truly effective treatment: depression is now the single most expensive condition in Western societies, and it has a worrisome and long list of comorbid companions, also with ferocious price tags both in dollars and in human suffering.  In other words, depression has substantial clinical and hidden mechanistic overlap with many other chronic diseases that are overwhelming Western healthcare systems, including on the more medical side DMII, CVD, neurodegenerative disorders, and on the psychiatric side, anxiety disorders, addictions, personality disorders, and PTSD.  

Depression also isn't simply an illness, as the core depressive mechanism may contain an adaptation aimed at the termination of intolerable and protracted forms of separation distress (an emotional state shared across all mammals), explaining why depression is ubiquitous not just in human but in all mammalian species studied so far.  It may reflect a fundamental vulnerability of the social brain, deprived of social connection and social comfort and safety.  The disinhibition of this conserved behavioral shutdown mechanism may create depressive illness, which often is not successfully treated simply with antidepressants, as this class of drugs has a low rate of achieving remission, helping to  explain why the incidence of depression in Western societies has steadily increased, despite an enormous rise in the prescription of popular antidepressants.  Depression shares a deep evolutionary relationship with other evolutionarily conserved behavioral shutdown mechanisms, most especially sickness behavior, but also hibernation, relationships consistent with growing evidence for a primary role of pro-inflammatory cytokines in depression.  Depression is prototypically triggered by social losses and other forms of painful social defeat, and the risk for depression may also be potentiated by many common pro-inflammatory lifestyle conditions and by the widespread social isolation in Western societies, where social media function as addictive substitutes for real intimacies, and where common social media conflicts serve to potentially deepen experiences of shame and rejection, both classically depressogenic.  Social isolation, loss of various work and social rewards and exposure to pro-inflammatory states all have been significantly exacerbated during the COVID 19 pandemic, helping to explain why COVID has seen an upsurge in depression across most societies.   

What does a more ‘social brain-centric’ view of depression do to our treatment algorithms and emphases?  It fundamentally, if not profoundly, changes them, but change is long overdue in view of the evidence that antidepressants have neither been proven safe in chronic administration nor are they terribly effective, particularly in mild to moderate depression – its most common manifestation – where they simply do not separate from placebo.  Additionally, in moderate to severe depressions where antidepressants do separate from placebo, ketamine and psilocybin, ECT and rTMS may be more effective than most mainline antidepressants, suggesting that antidepressants may actually have few good indications, contrasting painfully with their status as among the most prescribed drugs (21 million scripts in the last three months of 2020 up from 19 million during the same 3 month time period in 2019).  Most disturbing is the possibility that conventional SSRIs, SNRIs, TCAs, etc. may increase the vulnerability to depressive relapse upon discontinuation through uncharted mechanisms, creating ‘lifers’, as biopharma has been aversive to exploring this question adequately.  

We must change a losing game in relationship to this very common human vulnerability, reduce the shaming and stigmatizing associated with the diagnosis (both of which are ironically depressogenic), help depressed patients get out of traumatizing situations and social isolation that maintains the chronicity of depression, reduce pro-inflammatory lifestyle factors that also might be pouring gas on the depressive process, and help depressed patients to reconnect, repair their relationships when possible, or rebuild attachments from the ground up when necessary.  Instead of seeing depression as a sign of a mystified ‘chemical imbalance’, we should see it as a sign that individuals have been exposed to intolerable levels of psychic pain (compounded sometimes by concurrent physical pain), lack adequate social support, are suffering at the grinding intersection of severe stress and inflammation, and have lost basic hope. 

By Douglas F. Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.

In Part I, we looked at the criteria for major depression, the worrisome penetration of depressive illness into Western societies, and how the meme of ‘chemical imbalance’ hides depression's deep connections to separation distress, as the core mechanisms in depression may be evolutionarily conserved and aimed at terminating protracted separation distress and/or withdrawing from dominance conflicts that are going badly.  These two major adaptive benefits may explain why all mammals appear capable of some form of depression.  Depression may also have close mechanistic relationships with other conserved forms of behavioral shutdown – sickness behavior and hibernation.   

In Part II, we will zoom in on this evolutionarily close relationship between inflammation and depression and how inflammatory signals and stress axis activation are conjoined.  We examine evidence that psychiatry's monocular focus on neurochemical and genetic factors and its ignoring of what might constitute a ‘depressive environment’ obscures evidence of depression's connection to larger interpersonal and societal problems, to a deepening social isolation particularly in the United States, and to the growing evidence that declining social connection is actually a public health problem of the first rank.  As with the chronic diseases of aging, depression’s enormous footprint in modern societies indexes a significant gene-environment mismatch – an ‘evolutionary discordance, ’ in which our prosocial genome is being asked to function in isolation, or worse, in chronic social defeat (aka poverty).  We will look at the evidence that as our society has slid into deepening income inequality and declining social support, depression and what have been called ‘deaths of despair’ (deaths not normally attributed to depression but to OD, suicide and violence) have steadily increased, along with deaths from depression’s massive list of comorbidities.    

This general neglect of the environment and lifestyle within mainstream psychiatry has implications for improving our treatment paradigms, which have been dominated by SSRIs/SNRIs (80% of which are prescribed by PCPs), despite the evidence that they minimally separate from placebo in mild to moderate depression while the placebo mechanism declines in moderate to severe depression, allowing a clear impression of efficacy, yet with underappreciated and minimized toxicities.  Psychotherapy on the other hand is systematically shorted in the current treatment environment, despite evidence that psychotherapy protects against relapse whereas SSRIs etc. may actually predispose to relapse through poorly charted opponent process effects.  While cognitive behavioral therapy is widely regarded as some kind of gold standard, evidence supports no clear separation of efficacy between putative ‘types’ of psychotherapy – with acknowledgment that this technical/ theoretical orientation distinction may be ultimately specious, as therapist empathy, trustworthiness and insightfulness may be largest share of psychotherapy effect variance.  Focused work on precipitating stressors, especially classic depressogenic forms of separation distress, alleviation of concomitant social isolation/protection from any ongoing abuse or physical threat, exercise therapies, meditation and yoga disciplines, improvement in pro-inflammatory dietary patterns/dysbiosis, normalization of circadian dysfunction with improved sleep, and in more severe depressions, consideration to ketamine/psilocybin, rTMS, and ECT should all be part of the considered treatment space, not a reflexive and largely exclusive reliance on SSRIs and similar drugs.  For the most severely refractory depressions that fail multiple therapies including ECT, DBS may offer hope.  Once again, much better education of front-line clinicians within multiple disciplines, and education of the public such that patients can become more sophisticated consumers, may offer long-term correctives.