There has been a recent online storm about a review article that announced the death of the serotonin “chemical imbalance” theory of depression. In truth, the chemical imbalance theory has been on life support in psychiatry for over 2 decades but we forgot to tell the public we gave up on it long ago. Instead, the theory continued to be heavily pushed by drug companies to sell serotonin-selective reuptake inhibitor (SSRI) compounds. Apparently, the marketing efforts were successful. The Moncrief article highlighted a study that found 88.1% of respondents believed a “chemical imbalance” to be the cause of depression. In this next article, I will highlight the evolution of our updated understanding about the cause of depression.
My first impression when I read the current Moncrief review article was that the conclusion was not particularly controversial and it was a bit like crashing through an open door. The serotonin theory, and more broadly the monoamine deficiency theory which was first proposed in the 1960s, stated that depression is due to decreased function of monoamines which includes the neurotransmitters norepinephrine, serotonin, and dopamine. In the 1990s, the serotonin model was highly promoted in association with the marketing of antidepressants, known as selective-reuptake inhibitors or SSRIs which included Prozac, Zoloft, and Paxil. By the early 2000s, researchers already knew the idea that depression was caused by too little serotonin was naïve and turned their attention to the stress hypothesis, which posits that depression is caused when the brain’s stress machinery goes into overdrive. The most prominent player in this theory is the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus produces a substance, corticotropin-releasing hormone (CRH), which stimulates the pituitary gland, which in turn triggers the release of glucocorticoids, stress hormones such as cortisol, from the adrenal glands atop the kidneys. Abundant research shows that stress hormones are bad for nerve cells and have been shown to decrease the amounts of key ingredients in the chemical broth that keeps neurons healthy and sprouting, such as brain-derived neurotrophic factor (BDNF). The current thinking is that chronic stress decreases synaptic connections in the brain especially the prefrontal cortex and hippocampus; both of these areas have decreased volume and decreased function in Major Depression.
The stress hypothesis has gradually morphed into two other theories about depression: the neurotrophin hypothesis and the inflammatory hypothesis. Both these theories acknowledge that depression is not just a mental illness but a bodily one too and the mind-body connection is bidirectional. The neurotrophin hypothesis of depression proposes that most of the antidepressant effect (such as with SSRIs) comes from the increase in BDNF, expression and concentration, which improves neuronal plasticity by making more neuroconnections and replacing any damaged neuroconnections. BDNF is one of the good guys and is an essential growth factor that keeps the nervous system healthy for the entire life span. BDNF is not only found in the brain but is also expressed in the kidneys, retina, prostate, skeletal muscles and saliva. One easy way to increase BDNF is regular vigorous cardiovascular exercise (at least 3 days a week) in which BDNF is released in skeletal muscle tissue and can then travel in the blood and induce changes in the brain. Currently, scientists are experimenting with BDNF injections directly into the brain in humans and preliminary results have been positive although this obviously would never be practical on a broader scale. There are also 2 supplements that can enhance BDNF release: sodium butyrate and increased fiber in the diet.
The inflammatory hypothesis proposes inflammation somewhere in the body such as arthritis, gut microbiome, or obesity causes depression. Inflammation is the body’s first line of defense and then generates a systemic inflammatory response that communicates with the brain via the blood and HPA axis activation and can then result in changing mood and behavior. In one of my previous articles, I discussed how a low sugar diet, exercise, and getting enough sleep can also reduce chronic inflammation and improve mood. Research has shown that inflammation would only account for 1/3 of patients with depression but it’s twice as common in women than in men and can be associated with obesity, diabetes, metabolic syndrome and a history of trauma.
The discovery that low-dose ketamine, an anesthetic, produces rapid anti-depressant response by a novel mechanism (NMDA receptor blockade) is one of the most significant advances in the field in over 50 years. Ketamine may increase glutamate production which is another neurotransmitter in the brain and has anti-inflammatory effects on nerve cells by reversing the negative effects of chronic stress with cellular resilience as well as increasing BDNF release. Another rapid acting anti-depressant, Brexanolone was approved for the treatment of post-partum depression in 2019 by increasing GABA levels, a different neurotransmitter, in tissues that neutralizes the stress response and can reverse depression within 48-72 hours. Neither agent has any direct involvement with serotonin.
The serotonin model was a really important step forward in the middle of the 20th century. Current research continues to suggest that the brain’s serotonin systems play important roles in how our brains process different emotions. In fact, it would be surprising if such a widely distributed brain neuromodulator was completely uninvolved in the complex experiences that make up clinical depression. Today, it is largely accepted within psychiatry that depression is a heterogenous disorder with potentially multiple underlying causes: the biopsychosocial model, immune system, autonomic nervous system, and hypothalamic-pituitary adrenal axis, as well as primary brain systems, including the monoaminergic brain circuitries, and the neurotrophic support pathway (BDNF). The biopsychosocial model suggests that to understand a person medical’s condition like depression, it is not simply the biological factors just discussed to consider, but also the psychological (thoughts, emotions, and behaviors) and social (such as work issues, family circumstances, cultural) factors. Many psychiatrists wonder if depression should even be considered a single disease as just like cancer, one size does not fit all. Serotonin is still part of the depression story. It turns out one of the more promising agents still being tested for treatment of anxiety and depression is the mushroom, psilocybin, which is a serotonin specific agent. SSRIs, at least for now, still have role to play in the treatment of anxiety and depression even if our understanding of the biological causes moves away from theories focused solely on serotonin or even just the brain.