November 16, 2020 Mission 3:54 pm

Depression is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide, affecting an estimated 300 million people globally.

Approximately one third of patients with major depressive disorder are diagnosed with treatment resistant depression.

Symptoms vary, but generally, clinical depression is characterized by:

  • Persistent sadness
  • Fatigue
  • Disturbed sleep
  • Increased or decreased appetite
  • Feelings of guilt
  • Low self-worth


Beyond the subjective symptoms, depression is associated with disruptions in metabolic, hormonal, immune and inflammatory processes. And while the causes of depression are still being studied, depression is commonly understood to stem from a combination of psychological, physiological, and environmental factors. In some cases, depression may also be the result of conditions like Parkinson’s or hypothyroidism.

Nevertheless, though there is still much to learn about the origins and mechanics of depression, several key factors have been identified.

Unhealthy or extreme stress, particularly in early life, is a strong predictor for the development of depression in adulthood. When the body becomes stressed, the hypothalamus-pituitary-adrenal axis (HPA) becomes activated, trigging a complex set of interactions. The HPA axis releases corticotropin-releasing factor and arginine vasopressin into blood vessels connecting the hypothalamus and pituitary gland; these hormones then stimulate the production and secretion of adrenocorticotropic hormone (ACTH).

ACTH, in turn, promotes the release of glucocorticoid steroids such as cortisol, prolonged exposure to which has been linked to increased risk of depression. While various negative feedback loops – involving neurotransmitters like gamma-aminobutyric acid, norepinephrine, and serotonin – modulate HPA activation in healthy people, extreme or chronic stress appears to disrupt these processes, leading to the hyperactivity of the HPA axis seen in numerous psychiatric disorders, including depression.

Inflammation is also an important factor in the pathophysiology of depression. A relic of our ancient past, the human body exhibits an inflammatory bias – the tendency to respond to stressors with inflammation irrespective of their origin or nature. While helpful in the case of minor infections and injuries, chronic inflammation is associated with depression. In depressed individuals, consistently elevated levels of inflammatory biomarkers repeatedly trigger inflammation, leading to structural changes in the brain and disruptions in neuroendocrine functioning.

Several double-blinded, placebo-controlled studies have strongly suggested a causal relationship between inflammation and depression. When healthy adults were injected with lipopolysaccharide or interferon-gamma, levels of proinflammatory cytokines rose, leading to acute increases in depressive symptoms that coincided with peaks in inflammatory responses.

Rates of neurogenesis, the creation of new neurons, are another important factor in depression-related pathology. Ongoing neurogenesis is critical for establishing synaptic connections that improve neurological functioning throughout a person’s life. It is unsurprising then, that disturbed neurogenesis has been implicated in depression, and may also impede responsiveness to current frontline therapeutics. Impaired neurogenesis has been found to correlate with chronically high levels of stress hormone and depressive symptoms in mice models; adult mice that had been exposed to psychosocial stressors were found to exhibit both overall reductions in neurogenesis and reduced survivability of new cells. Lower rates of neurogenesis occur due to hyperactivity of the HPA-axis, a paucity of neurotrophins like brain derived neurotrophic growth factor, and chronic inflammation.

Finally, genetic predisposition is responsible for approximately one half of the overall risk of developing depression. One meta-analysis that drew on data from over 800,000 patients identified 269 genes associated with depression, many of which influence formation of synapses, neurotransmitter production, and metabolic function. Importantly, genetics are intimately linked to circadian rhythms, the autonomic regulatory processes that regulate sleep-wake cycles, and which are responsible for up to 40% of gene expression in the brain, liver and muscles. Disruption of circadian rhythms strongly influences the development of depression.

Two genes in particular, NPAS and CLOCK, as well as the proteins they code for, Clock and Npas, seem to exert decisive influence on circadian rhythms; disruptions in either have been shown to result in sleep disturbances in mice. This is significant in light of one study examining the genomics of more than 500 Spanish adults, which found that those who carried two of the G alleles of the NPAS gene – a condition associated with issues in sleep – exhibited a nearly 3-fold increase in depression risk; those who carried just one saw their risk increase almost 1.5 times.

Other potential causes and risk factors for depression include: side effects from pharmaceuticals, particularly beta-blockers, calcium channel blockers, and angiotensin II inhibitors; dietary habits that lead to deficiencies in nutrients that modulate inflammation, neurogenesis, and metabolism, as in the case of vitamins B6 and B12, and omega-3 fatty acids; and a lack of microbial diversity in the gut, which contributes to changes in immune function, decreased mood, and further disturbances in dietary preferences, leading to a continual cycle of inflammation and depression.

Unfortunately, the prognosis for depression is not favorable. For the more than 340 million depression suffers, currently available front line treatments – typically selective serotonin reuptake inhibitors (SSRIs) coupled with cognitive behavioral therapy – have moderate response rates of 40-50%, with remission rates as low as 30%. Indeed, more than 80% of people who experience one episode of depression will continue to suffer from the condition six years later. Moreover, SSRI’s and other frontline treatments come with a bevy of potential side effects, ranging from fatigue and hair loss to hypertensive crisis and mania.

Behavior-based treatment pathways do exist (with varying levels of efficacy). For example, numerous randomized controlled studies have shown exercise mitigates depressive symptoms and assists with recovery, particularly in the case of moderate- to vigorous-intensity aerobic exercise. Dietary modification has also been shown to be effective: one 12-week randomized controlled trial showed that changes promoting healthy nutritional choices were more effective than social support in ameliorating depressive symptoms. Finally, meditation has also been found to be a viable option, with one meta-analysis covering more than 3500 patients finding that mindfulness mediation was moderately effective at alleviating anxiety and depression.

But perhaps the most promising alternative treatment route is found in the form of psychedelic drugs. One randomized, double-blind, cross-over trial found that psilocybin – the active ingredient in magic mushrooms – ameliorated symptoms of depression and anxiety in patients with life-threatening cancer, with effects persisting for up to six-months after treatment. Another psychedelic-type drug, ketamine, has shown efficacy at six hours that is equal to the effects of other antidepressant medications at six weeks, with responses in more than 80% of patients. However, despite positive early signals, additional research is necessary to establish the safety and efficacy of such interventions.

In summary, depression is a complex condition that we have only begun to understand fully, with environment, genetics and numerous other factors implicated in its etiology. Moreover, while current treatments are effective for some, only a minority of people with depression achieve remission. And while alternative treatments do exist, only a few have been shown to be effective to any significant degree. Thus, research into novel therapeutics like psilocybin, ketamine and others, is critical if we are to provide relief to the estimated 100 million people living with treatment resistant depression.


Receive the latest news on atai and innovations in the space.