Depression and hopelessness


Up until the early years of the twentieth century, depression was labeled “melancholy.” It was the torpor and listlessness of a woman who, incapacitated by feelings of hopelessness and worthlessness, could not take care of her children or manage her household. It was the man who, unable to hold a job and support his family, turned to drink.

Anyone who has experienced depression—not just a transient blue mood, but the incapacitation, hopelessness, and self-loathing of genuine depression—understands that this is not just a passing bit of feeling blue, but a real, sometimes life-threatening, questioning of self-worth and the value of life.

This is not a small problem. The World Health Organization estimates that 322 million people suffer depression around the world, or 4.4% of all people at any one time. Over a lifetime, of course, the number is far greater. Nonetheless, this sounds like a gross underestimation to me, judging by just looking at the people around you: depression is common. It may not be severe enough to prompt someone to seek the counsel of a doctor or psychiatrist, but I believe it is more common than suspected. It can fluctuate, it can come and go, but it surely afflicts more than 4.4% of people. It’s also increasing, outpacing the growth of the population: more and more people are experiencing depression.

Insight into this common and troublesome condition has evolved over the generations. Let’s consider a brief timeline of milestones in the understanding of depression:

  • 4th century B.C.—Greek physician Hippocrates offered his humoral theory of disease, the theory that diseases originated with disruption of the four humors: phlegm, blood, yellow bile, and black bile. It was this notion of excessive “black bile” causing depression that Hippocrates labeled melaina chole, that led to the Anglicized word, melancholy.
  • Late 19th century—Dr. Charles Mercier, psychiatrist and one of the pioneers of forensic psychiatry, proposed that melancholy was a disorder of brain physiology, setting the stage for the next 100 years of psychiatric thought on depression.
  • Early 20th century—Austrian neurologist, Dr. Sigmund Freud, promoted the idea that depression (and other disorders of the psyche) were rooted in childhood sexual (mis)experiences and pioneered concepts such as the interpretation of dreams and repression, the suppression of painful childhood memories that manifest as various adult behaviors.
  • Mid and later 20th century—The concept of “chemical imbalance” underlying depression became popular, justifying the proliferation of antidepressant medications targeting the readjustment of brain emotion-mediating chemicals such as epinephrine, norepinephrine, serotonin and others.
  • 1952—The first Diagnostic and Statistical Manual, DSM-1, that has become the cornerstone reference for psychiatric diagnosis and treatment, catalyzed the shift from melancholy as an emotional disorder to that of depression, a medical disorder to be treated by methods such as electroshock therapy and psychopharmaceuticals.
  • 1990s—The emergence of functional MRI brain imaging revealed the brain correlates of depression, such as decreased volume of the prefrontal cortex, anterior cingulate cortex, thalamus, and hippocampus—documenting that depression was not just an emotional state, but a measurable disease of the brain. It showed that people who experienced childhood trauma, for instance, had unique physical and physiological changes in brain structure and physiology.
  • 1990s and 21st century—MRI and other investigations made it clear that depression featured myriad disruptions in brain neurochemistry, immune response, hormonal disruptions, and inflammation. In other words, a change in brain neurochemistry was only one facet of a much more complex process. Explorations of the hypothalamic-pituitary axis (HPA axis) involving cortisol release in about 50% of people suffering depression made it clear that, while the HPA axis was involved, the relationship was complex, sometimes involving activation, sometimes involving deactivation.
  • 2010 and onwards—It became clear that people with major depression expressed higher levels of inflammation, such as higher C-reactive protein, IL-1 beta, IL-6, TNF and others. It also became clear that, while some people responded to conventional antidepressant medication such as selective serotonin reuptake (SSRI) inhibitors such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), and sertraline (Zoloft), those who did not respond had higher levels of inflammatory markers.
  • 2010 and onwards—People who respond to conventional antidepressants also show improvements in inflammatory and immune markers.

2015 and onwards represents a period of unprecedented discoveries in depression, with numerous observations on the microbiome as the seat of much depressive phenomena. Among the observations that have been made:

  • Transfer of fecal material from a depressed human to a mouse generates depressed behavior.
  • The so-called “gut-brain axis” is bidirectional: the gut sends signals (via vagus nerve and various metabolites) to the brain, the brain sends signals to the gut (via neurochemicals, vagus nerve, HPA axis).
  • There appears to be a microbial “signature” in depression that includes relative lack of Faecalibacterium, Ruminococcaceae, Lachnospiraceae, Clostridiaceae, Blautia, and Dorea, along with increased Proteobacteria (the species of dysbiosis and SIBO).
  • People with depression express higher antibody levels against lipopolysaccharide, LPS, a toxic component of Proteobacteria.
  • People with depression and anxiety harbor microbes that generate LPS.
  • Injection of LPS into healthy volunteers promptly generates the emotions and functional MRI “signatures” of depression.

Surely, depression has numerous causes. For one person, it could be childhood trauma. For another, it could be some social or financial situation—a bad marriage, money worries. But the evolution of theories to account for depression that appears to lack an external cause is increasingly pointing towards the microbiome and the endotoxemia that accompany it. It therefore means that addressing the microbiome and the intestinal barrier to endotoxin can make a major contribution to managing or relieving depression. These are issues that I shall be discussing in future.

This is not just some intellectual exercise. Understand the details of the problem, and it can point us towards more effective solutions.