When Depression is an Inflammatory Disorder
The neurotransmitter deficiency hypothesis of depression, as a unicausal model, is growing ever more wobbly under the accumulating weight of a variety of disconfirming findings – contradictory basic science data, studies of monoamine reuptake inhibitor efficacy that show these drugs to be scarcely better than placebos in many patients, and the emergence of more compelling etiological theories.
The inflammation hypothesis is perhaps the hottest new account of depression (at least the one with most calor). Over a decade or so there has been an explosion of data emerging from many quarters suggesting that chronic low-grade systemic inflammation plays a significant role in major depressive disorder, as both cause and effect. But as with any hypothesis that seems to have robust explanatory power, there is the temptation to wield it in a reductionist manner – to turn it into the next medical catechism, or “normal science,” as Thomas Kuhn would put it.
So, if not all patients suffering from inflammation get depressed, and not all depressed patients show signs or describe a history of inflammation, we must wrestle with a crucial question: when is depression an inflammatory disorder? This is precisely the issue taken up in this excellent review article by Charles L. Raison and Andrew H. Miller of the Mind-Body Program in the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine. In one study they lumped all treatment-resistant depressed patients together, and found that treating them with an anti-inflammatory drug had little effect. However, when they separated out those subjects who had elevated inflammatory markers (in this case, CRP >5), the drug, infliximab (a TNF alpha blocker), worked as well as any antidepressant. Interestingly, patients with a low baseline level of inflammation were actually rendered more depressed by the anti-inflammatory drug.
This is a powerful affirmation of a foundational tenet of functional medicine: the importance of considering a patient's biochemical individuality in any treatment. But it must also be pointed out that such a drug did not treat the cause of the inflammation. Unlike the more gentle, pleiotropic, non-toxic anti-inflammatory botanicals and nutrients with which humans evolved, infliximab is an anti-inflammatory assault weapon, a guided missle aimed at a singular molecular target. And it can produce serious collateral damage, such as life-threatening infection and malignancy. To be fair, the aim of their study was not to find an optimal treatment, but to clarify the relationship between inflammation and depression.
Also, the authors are careful to point out that inflammatory cytokines have multiple functions, harmful and vital, depending on their levels. Even TNF alpha, at low levels, can function as a neurotrophic factor. And, of course, without the capacity to synthesize and deliver adequate amounts of these cytokines, our own defenses against microbes and tumors would be severely impaired. But even mild elevations can become excitotoxic and neurotoxic in the brain. One lesson here is that anti-inflammatory interventions (especially drugs) must be based on lab data whenever possible. That is why at the Mind-Body Clinic all patients with mood disorders are assessed for excessive levels of inflammatory markers as part of our routine comprehensive evaluation. And when we do find evidence of an inflammatory component, our aim is to identify and treat the upstream cause, not just it's downstream effects.
To their credit, Raison and Miller do hold in mind the complex, multifactorial nature of depression. They describe how variables such as early life adversity (attachment trauma, loss, neglect, abuse), increased visceral fat, microbial infection, evening cortisol levels and other manifestations of maladaptive stress, and sleep deprivation interact with inflammatory processes in the etiology of depression. (To these we would add MTHFR status along with variations in other genes, nutrient levels, toxicant exposure, and psychodynamic processes that arise from the conflictual inner worlds of patients.)
One fascinating interaction between these variables Raison described in a recent Medscape webinar concerned the complex association between early life adversity, inflammation, and depression. He outlined a series of prospective studies that attempted to disentangle this association. In the absence of early adversity, inflammation actually lowered the risk for depression six months later. (Perhaps the transient elevation in cytokines exerted a neurotrophic effect there.) On the other hand, in the context of early adversity, inflammation was followed six months later by depression.
It appears that the stress of early adversity can program the body and brain to keep inflammation elevated, producing changes in the brain that in turn predispose toward depression. The work of investigators like Raison and Miller are expanding the ever-growing scientific foundation of the systems biology paradigm known as functional medicine, which sees neuropsychiatric conditions as perturbations of a network rather than as manifestions of disordered parts treatable in isolation.