The Inflamed Brain: Unravelling the connection between inflammation and depression

If some cases of depression are caused by inflammation and inflammation is caused by poor diet and lifestyle and social isolation, the solution is obvious: drugs!

It's a truism among medical researchers that it takes an average of 17 years for evidence gathered through that research to change clinical practice. And what that means, is that practitioners who are adhering to the norms and guidelines of their professions continue to deploy useless, inferior or counterproductive investigations and treatments in their care of sick, injured and suffering people, for nearly two decades after research has demonstrated that these interventions should be abandoned or replaced.

I was reminded of this lengthy research-to-practice lag by a viewpoint published in JAMA Psychiatry this week. Titled 'Should Inflammation Be a Specifier for Major Depression in the DSM-6?', the opinion piece argues that the upcoming sixth edition of the psychiatrists' 'bible', the Diagnostic and Statistical Manual of Mental Disorders (DSM-6), should carve out a subtype of depression which is specified by elevated inflammatory markers, and "associate[d] with a clinical phenotype characterized by symptoms including anhedonia [inability to experience pleasure from or interest in activities previously enjoyed], fatigue, psychomotor slowing [slowing down of thought, speech and physical movement], appetite disturbances, and impaired sleep."

The authors assert that identifying a particular category of depression with a distinct presentation, and with inflammation as its underlying mechanism, would help practitioners to provide more tailored care to people suffering from this subtype, for whom conventional antidepressant drugs don't work as well¹ whereas certain anti-inflammatory agents show promise.

More generally, they argue that

"Specifying mechanisms in the DSM-6 may not only help guide clinical care but may also facilitate research by reducing heterogeneity of the disorders, ultimately supporting the development of targeted therapeutics and precision psychiatry."

Should Inflammation Be a Specifier for Major Depression in the DSM-6?

By "heterogeneity of the disorders", the authors mean that the diagnostic categories of the DSM - such as 'disruptive mood dysregulation disorder', 'generalized anxiety disorder' and 'adjustment disorder' - are simply grab-bags of symptoms arrived at by 'expert' consensus, with considerable overlap between supposedly distinct diagnoses, and with no proposed biological or psychosocial mechanism underlying them.

Reading this reminded me of an article I wrote back in 2014 titled ‘Depressed’ or just going through a rough patch – have you been misdiagnosed? In this article, I discussed an editorial written by then-director of the (US) National Institute of Mental Health (NIMH) Thomas Insel:

"The National Institutes for Mental Health (NIMH), the US government agency that provides grants for the study of mental illness, has dumped the 'bible' of psychiatric diagnosis, the DSM (Diagnostic and Statistical Manual of Mental Disorders), which is published by the American Psychiatric Asssociation.

The DSM is one of the two manuals used by doctors in Australia to diagnose mental and psychological disorders based on symptoms, descriptions and markers of conditions. From this diagnosis flows a raft of consequences, including treatment plans, provision of special education services to diagnosed children, and even decisions in legal cases.

So why is the NIMH, in the words of its director Thomas Insel, 're-orienting its research away from DSM categories'? Quite simply, because the criteria used for diagnosis of the conditions the DSM describes suffer from a 'lack of validity'.

Yes, you read that correctly. The director of the most powerful mental health research funding agency in the world says that the psychiatrists' 'bible' is more like a fairy story than a textbook.

Insel went on to say,

'Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment. Patients with mental disorders deserve better'."

'Depressed’ or just going through a rough patch – have you been misdiagnosed?

Insel's editorial, published on April 29, 2013, was subsequently removed from the NIMH's website but very fortunately, not before being archived by the Wayback Machine. I encourage you to read it in full, and then reflect on the fact that 12 years (which is not quite 17 years but getting darn close!) after the director of the world's major funder of mental health research wrote that DSM categories are not valid - meaning that they don't identify what they purport to - and are therefore not useful for guiding research into diagnosis or treatment of psychological conditions, clinicians are still using the DSM-V to classify their patients' suffering.

And of course, diagnosis leads directly to the selection of treatment regimens. If you're diagnosed with depression, it's antidepressants for you, regardless of whether you began feeling very low after you lost your fortune, your spouse cheated on you with your best friend and your horse done left you (in best country music fashion); or whether you woke up one morning and found that the whole world had turned grey overnight and you just couldn't get out of bed. (Ask yourself whether these two presentations of depression are likely to have much in common with each other, and therefore, whether the approach to treatment should be the same. Obviously not.)

The authors of the JAMA Psychiatry viewpoint discuss several lines of evidence that buttress their claim that elevated blood levels of inflammatory markers are pathognomic (specifically characteristic or indicative) of a distinct subtype of depression:

• Patients with major depression have been shown in multiple studies to have elevated biomarkers of inflammation in their blood, including C-reactive protein (CRP), interleukin 6 (IL-6) and tumour necrosis factor (TNF). Approximately 25 per cent of depressed patients have low-grade inflammation, indicated by a CRP greater than 3 mg/L.

• When non-depressed people are given pro-inflammatory drugs such as interferon α (IFN-α), between 30 and 50 per cent develop depressive symptoms.

• When depressed people are given anti-inflammatory drugs, their depressive symptoms decrease - regardless of whether or not they had some other illness that might be alleviated by anti-inflammatories.

• A recent study using advanced multiomics (a biological analysis approach which uses AI to analyze and combine multiple types of molecular information within individual cells, including the genome, epigenome, metabolome, and microbiome) revealed that TNF, interleukin 1β (IL-1β), and a major IL-6 signalling molecule, are the principal upstream regulators and transcription factors involved in the pathophysiology of depression.

• In both humans and non-human animals, individuals with increased peripheral blood inflammatory biomarkers display 'sickness behaviour' characterised by anhedonia, fatigue, psychomotor slowing, appetite disturbances, and impaired sleep.

• Administration of inflammatory mediators including IFN-α, endotoxin, and typhoid vaccine engages neurotransmitters and neural circuits that are believed to be involved in depression, particularly those related to motivation and motor activity.

• Elevated CRP (indicating inflammation) is associated with decreased functional connectivity in brain reward circuitry, and with anhedonia and decreased psychomotor speed.

Taken together, the authors argue that depression characterised by low motivation, anhedonia and psychomotor slowing represents a distinct subtype, which is not just accompanied by, but specified by inflammation

.

So far, so good. I welcome the recognition that inflammation plays a pivotal role in depression; I've written extensively about this connection, in Inflammation: why you’re fat, sick, tired, depressed and in pain… and what to do about it, Cholesterol and depression: What’s bad for the heart is bad for the brain, Hearts, minds and bodies on fire: Loneliness, social isolation, inflammation and COVID-19, and The good news about depression – Part 2, and Part 4.

But I part company from the authors of the JAMA Psychiatry viewpoint, and indeed from former NIMH director Thomas Insel, when it comes to interpreting the significance of the inflammation-depression connection, and its implications for treatment approaches. In his 2013 editorial, Insel stated that "Mental disorders are biological disorders involving brain circuits that implicate specific domains of cognition, emotion, or behavior", and that "Mapping the cognitive, circuit, and genetic aspects of mental disorders will yield new and better targets for treatment."

In other words, according to Insel, human beings are just very complicated machines with parts that go awry - by becoming inflamed, for instance - for reasons that are largely unknown and not really worth investigating (except that our genes are probably to blame in some way). One of the manifestations of this malfunction are "mental disorders" such as depression and anxiety, and we will find better treatments for such disorders by doing lots of sciencey stuff involving brain scans and genome sequencing and studying the responses of people with "mental disorders" to various stimuli.

Heaven forfend that we should simply ask these suffering individuals why they are feeling so terrible. It's not like they could possibly have any insight into their own condition, after all.

"It's among the intelligentsia that we often find the glib compulsion to explain everything and to understand nothing."

Joost Merloo

Likewise, the JAMA Psychiatry viewpoint authors simply lay out the evidence that people with major depression have elevated inflammatory markers, without asking the obvious question: why are they inflamed?

There's extensive evidence, for example, that diets high in saturated fat cause endotoxaemia (elevated levels of endotoxin in the blood) which - as acknowledged in the JAMA Psychiatry viewpoint, in turn triggers inflammation. And, as I wrote in Eat your way to better mental health?, "high consumption of refined grains, sugar, fat and processed meat is associated with increased levels of low grade inflammation which results in atrophy of brain regions linked with depression". Obesity has long been known to be associated with elevated inflammatory markers, and conversely, weight loss results in decreased inflammation levels. Diets high in whole plant foods - fruits, vegetables, legumes, whole grains, nuts and seeds - exert anti-inflammatory effects by supplying micronutrients, antioxidants, and prebiotics that foster the growth of beneficial gut bacteria.

You know what else is associated with inflammation? Social isolation and loneliness (perceived social isolation). Socially isolated people have elevated CRP levels, while lonely people have elevated IL-6. Remember, these are the very markers of inflammation singled out by the JAMA Psychiatry editorialists as being elevated in people with major depression, and yet they don't devote one word of their piece to the role of social disconnectedness in driving both inflammation and psychological distress, or the use of social reengagement strategies to alleviate them.

What therapeutic strategies do they focus on? You'll never guess. I'll give you a hint: the Conflict of Interest Disclosures reveal that the authors have received grants and funding from a plethora of pharmaceutical and biotech companies including Janssen, GlaxoSmithKline, Boehringer Ingelheim and Pfizer; a company which runs clinical trials; and the GlaxoSmithKline-funded Wellcome Trust. Can you guess now? Of course, it's drugs. Lots of lovely drugs. Primarily anti-inflammatories - especially anticytokine treatments like monoclonal antibodies, which are far more lucrative to produce than generics like boring old aspirin or ibuprofen - but also dopamine-boosting agents like levodopa and κ-opioid receptor antagonists.

Along with the drugs, they suggest "neuromodulation of corticostriatal reward circuits" which is code for deep brain stimulation (which involves drilling small holes in your skull in order to implant electrodes adjacent to specific deep brain structures, that deliver an electrical current directly into your brain), and transcranial magnetic stimulation (which uses a magnetic coil to stimulate particular regions of the brain). Because nothing speaks to 'addressing the underlying causes of depression' like drilling holes in people's heads and messing with the electrical circuitry of their brains.

In their defence, they do include the briefest of brief mentions of a non-drug, non-device treatment modality: "psychotherapeutic strategies focused on motivational anhedonia such as behavioral activation." Behavioural activation involves scheduling and carrying out meaningful activities in order to boost the depressed individual's experiences of pleasure and mastery, and it's very effective even for people whose depression has not responded to other treatment approaches.

So that's ten words out of a two-page article that grudgingly acknowledge that anything other than drugs and devices might be able to alleviate depression, by, among other mechanisms, tamping down inflammation. No mention of the role of diet, physical activity, building social connections, and spending time in nature on reducing inflammatory markers and easing depressive symptoms. And definitely no mention of the fact that depression occurs for a reason.

As I wrote in The depression misconception, depression is failure feedback. It's an expected, and - at least initially - both functional and adaptive response to a person's failure to achieve important life goals (e.g. romantic rejection, unemployment), or the loss of something that helps one achieve one's important goals (e.g. being widowed, becoming disabled). Being physically unhealthy, obese, sedentary and/or socially isolated and deprived of contact with nature increase the probability of a bout of depression that was triggered by some kind of failure, turning chronic.

Hence it makes perfect sense to incorporate diet and lifestyle change, social reengagement and nature therapy into a therapeutic protocol for depression, along with behavioural activation. These modalities all reduce inflammation and help to relieve the symptoms of depression so that the depressed individual can undertake effective therapy - that is, therapy that focuses on forthrightly facing the failure or loss that precipitated the depressive episode; carefully analysing its causes, discarding inaccurate interpretations along the way; forging a sense of meaning or purpose out of the failure or loss; and developing and implementing a realistic plan to solve the problems created by the failure or loss.

Or you could just go on viewing yourself as a person with a "mental disorder", take drugs for the rest of your life, and have electrodes implanted in your brain. Your choice, I guess.

For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine

1. I seriously doubt that conventional antidepressants truly 'work' for anyone at all; as I wrote in ‘Depressed’ or just going through a rough patch – have you been misdiagnosed? "Irving Kirsch has argued convincingly in his book The Emperor’s New Drugs, [that] careful study of clinical trials of antidepressant drugs indicates that they are no more effective than placebos." It seems likely that people with depression associated with high inflammatory markers are less susceptible to the placebo effect.