- The serotonin theory of depression has been called into question recently.
- Major depressive disorder should not be treated as though it has a single etiology.
- Neuroinflammation may play a role in some cases of MDD.
A bombshell went off in psychiatry last year when Moncrieff and colleagues’ systematic review in Molecular Psychiatry concluded, “We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.” Their review revealed that there is a lack of good science to support the notion that major depressive disorder (MDD) is due to low levels of the neurotransmitter serotonin. More importantly, it calls into question the use of antidepressants designed to address this deficiency (selective serotonin reuptake inhibitors [SSRIs]), even though these drugs have been prescribed to tens of millions of people over the last 35 years.
Within the press, the conclusion was clear: If the serotonin theory of depression is not true, then it’s a waste of time to prescribe these drugs to patients with MDD.
Clinicians have been a bit more ambivalent. Despite the absence of empirical evidence to support the serotonin theory, we have seen SSRIs work, especially when used with psychotherapy and lifestyle changes. Even if we don’t fully understand how these medicines work, there is clinical evidence that patients with MDD have experienced improvements.
So They Both Work and Don’t Work?
Yes. Ever since being developed in the 1950s, researchers have known that antidepressants do not work for everyone, that the placebo effect can heavily influence outcomes, and that many patients with MDD (perhaps as high as 30 percent) have what is known as "treatment-resistant depression." With response rates to conventional antidepressants being somewhere between 40 and 50 percent, and remission rates significantly lower, this strongly suggests that MDD does not have one etiology that can be corrected, which is 1) why MDD is so difficult to treat, and 2) why no one treatment will ever cure it.
This is true of just about all psychiatric conditions—they rarely have just one cause. Far more frequently, conditions arise due to numerous psychological, environmental, and biological factors. While symptoms may be similar from patient to patient, the causes of the symptoms can be dramatically different. Understanding these underlying factors is crucial for clinicians when deciding on specific treatment regimens for patients because they are key determinants in predicting treatment efficacy.
Put simply: Just because a treatment worked for one patient does not mean it will work as well for anybody else. Each patient must be treated uniquely.
Treating “Endogenous” Depression
Characterized as a disorder that causes persistent low mood and a reduced ability to feel pleasure (anhedonia), as well as several other symptoms, such as weight loss, insomnia, hypersomnia, fatigue, and suicidal ideation, MDD can drain life of joy and rob patients of years of their lives.
For some, depressive symptoms can be related to negative affect and stressful life events. Others may struggle with a combination of adverse childhood experiences and genetic vulnerabilities. For others, there are no external “reasons” for MDD; it seems to be something innate within them. Consequently, this latter subtype of depression was once called "endogenous depression" or "melancholia."1
Since at least the 1950s, many within the field of psychiatry have presumed that this endogenous subtype of MDD is distinct from other types of depressive disorders and that it could be explained by abnormalities in neurotransmitter signaling—the common euphemism of “chemical imbalances.”
What if they were right? What if these “chemical imbalances” are only occurring in a small subset of patients with depression, but being prescribed to all patients, thereby explaining the confusing data? What if the far more frequent cause of depression is linked not to neurotransmitter dysfunction, but neuroinflammation?
What Is Inflammation?
Inflammation occurs when the body’s immune system responds to injury or infection. If you scrape your arm, it will hurt, turn red, and maybe even be warm to the touch. That redness and heat are signs of inflammation.
Ordinarily, inflammation is not problematic. In fact, it is an absolutely necessary process because it prevents further damage to cells by clearing infections, irritants, and any dead or damaged cells. Once cleared, the inflammation dissipates, and things return to normal. This is true should the inflammation be caused by something that is localized—such as a scratch on the arm or a minor bacterial infection—or something that is more systemic, such as oxidative stress.
Oxidative Stress, Inflammation, and Neuroinflammation
Oxidative stress is a natural phenomenon that occurs when free radicals are released during normal processes (digesting food, breathing, turning fat into energy, etc.), and these free radicals are typically eliminated by the body’s immune system. However, the immune system does have its limits and it can become overwhelmed by oxidative stress due to a nutrient-poor diet, limited sleep, a lack of exercise, and exposure to pollution. The result is chronic systemic inflammation, which produces pro-oxidant proteins, which causes more oxidative stress, which causes more inflammation.
While there are systems within the body designed to quell this vicious cycle (such as the endocannabinoid system), it can spin out of control and eventually affect the brain. Persistent inflammation eventually makes the blood-brain barrier more permeable, allowing for the passage of pro-inflammatory cells that activate the immune system within the brain, leading to neuroinflammation.
In addition to being central to the pathophysiology of neurodegeneration and multiple neurological disorders, mounting evidence suggests that neuroinflammation leads to the subjective experience of symptoms like anxiety and depression. Moreover, research is suggesting that some cases of MDD might be treated by targeting and reducing neuroinflammation.
As interesting and potentially groundbreaking as these findings are, the fact of the matter is that MDD is a multidimensional disease. Even if it turns out that neuroinflammation is a cause of MDD, it would be only one among many. Therefore, anti-inflammatory medications that target neuroinflammation will only work for a subset of individuals in the best of scenarios. As we come to better understand the complexity of depression, it is vital that we remember the old adage, “Treat the patient, not the disease.”
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