Despite the recent increase in its prevalence, depression is not a newly identified condition.
References to depressive illness or melancholia were common among the medical texts of the ancient Greek physicians, who believed that depression arises from disturbances in the natural balance of the body’s four fluids, or humors, which included blood, phlegm, yellow bile, and black bile.
To their thinking – the black bile – produced a dark state of melancholia, a construct that dominated medical thought until the 1600s.
Today, the causes of depression still remain unknown but are widely believed to be multifactorial, coming from a combination of psychological, physiological, and environmental elements.
In addition, we know that having a chronic medical condition increases a person’s risk of developing depression.
Depression can also be a symptom of certain medical conditions, such as Parkinson’s disease, multiple sclerosis, hypothyroidism, or Cushing’s disease.
Here’s what we know that may be some of the causes of depression
"I think the saddest people always try their hardest to make people happy because they know what it's like to feel absolutely worthless and they don't want anyone else to feel like that"
Trauma or childhood trauma –
Emotional or physical trauma, especially early in life, plays a key role in the pathophysiology of depression.
It is a robust risk factor for developing depression in adulthood, especially in response to additional stress.
ACEs, or adverse childhood experiences, are potentially traumatic events that occur in childhood.
ACEs can include violence, abuse, and growing up in a family with mental health or substance use problems.
The toxic stress from ACEs can change brain development and affect how the body responds to stress.
ACEs are linked to chronic health problems, mental illness, and substance misuse in adulthood.
The body responds to stress by activating a complex set of self-regulating, adaptive processes that include both behavioural and physiological components to ensure our survival.
The HPA axis, or hypothalamus-pituitary-adrenal axis, is an interface between stress and brain function.
Your HPA axis is activated when the hypothalamus (area in the brain) releases the neurohormones corticotropin-releasing factor and arginine vasopressin into the blood vessels that connect the hypothalamus and the pituitary gland.
Those two neurohormones stimulate the anterior pituitary gland to produce and secrete adrenocorticotropic hormone into the bloodstream, which in turn promotes the synthesis of other hormones, mainly cortisol.
You may know cortisol as the main “stress hormone”.
Having cortisol release for too long increases the risk of developing depression.
Several other neurotransmitters – GABA, endogenous opioids, norepinephrine, and serotonin, work in beautiful symmetry to modulate the activation of your HPA axis.
We know that hyperactivity of the HPA axis is commonly seen in depression.
We can look at the study that involved rodents and non-human primates when the young animals that were separated from their mothers for long periods exhibited HPA axis activity changes that persisted into adulthood, it resembled those observed in depressed people.
Another study looked at childhood sexual abuse exhibited enhanced HPA axis activation in adulthood
Inflammation
Another key player in the cause of depression is inflammation.
Inflammation isn’t good or bad but depends on the context and a few other factors.
When you sprain your ankle while walking on an uneven surface, you’ll have an inflammatory response, which is beneficial for healing.
Inflammation becomes a problem when it is prolonged.
It’s a biological response that developed humans’ ancient past, in which regular exposure to different pathogens dictated high coordinated behavioural and immune responses for our survival – this is good.
Dr. Charles Raison and Andrew Miller call this an inflammatory bias.
Our bodies have a propensity to launch an indiscriminate response to a stressor – regardless of its source.
We have acute inflammation, this occurs after minor injuries or infections. You can tell this one by local redness, swelling, or fever.
Chronic inflammation occurs deeper at the cellular level in response to internal and external stressors, which are often invisible.
Chronic inflammation is instrumental in the development of many major diseases, including depression.
A study in 2018 demonstrated that 4 biomarkers were able to accurately and reliably distinguish among patients with major depression, bipolar depression, and healthy controls
The 4 biomarkers included elevated levels of dopamine, GABA, Tyramine, as well as low kynurenine levels.
There is another new test that may provide information on the diagnosis of depression and it looks at BDNF.
Elevated biomarkers of inflammation, which are commonly observed in people who have depression, chronically activate the body’s inflammatory response system, promoting the development of depressive symptoms and inducing changes in the brain and neuroendocrine function.
There is compelling evidence that suggests there may be a causal effect of inflammation and depression.
At least two double-blinded, placebo-controlled studies investigated the effects of injecting healthy adults with either lipopolysaccharide (which is an endotoxin of a bacterial cell membrane that elicits an immune response) or interferon-gamma, a proinflammatory cytokine.
The injection of either endotoxin or the interferon-gamma increased the study participants’ circulating levels of proinflammatory cytokines, including IL-6 and tumor necrosis factor-alpha.
In both of the studies, the participants experienced an acute increase in depression symptoms, social disconnection, anxiety, and a lack of reactivity to pleasurable stimuli that seem to coincide with the peak of the proinflammatory response.
Neurogenesis | Brain growth
Neurogenesis is the birth and growth of new neurons, which was originally believed to be absent in the adult brain.
Broadly speaking, neurogenesis isn’t just the birth of new nerve cells, it can also encompass neuronal differentiation, survival, maturation, and the integration of new neurons.
Any analogy of neurogenesis is similar to gardening. We prune the dead or dying branches to allow for new growth of life.
For a long time, we thought that we were born with the number of brain cells, and every drink, drug, or concussion killed the cells and we would never be able to get those cells back.
Through the understanding of the brain and neuroanatomy that we realized we were wrong. Our brain is capable of growing and pruning new synaptic cells – throughout our life!
After about the age of 25, neurogenesis is slower compared to infants and teens.
Neurogenesis is essential during embryonic development but also continues in certain brain regions throughout our life.
In particular, areas of the hypothalamus and the olfactory bulb serve as “neurogenic niches”.
A neurogenic niche is a region where neurogenesis takes place.
Problems with adult neurogenesis and subsequent connectivity losses or failures have been implicated in depression and may further impede the responsiveness of antidepressant therapists.
Mice with impaired adult neurogenesis exhibit sustained stress hormone levels and display depressive-like symptoms.
When mice were exposed to an acute psychosocial stressor at the time of nerve cell generation, fewer new cells were produced.
If the stress occurred after nerve cell generation, the cells were less likely to survive long-term.
There are several factors the contribute to impaired neurogenesis, including hyperactivity of the HPA axis, insufficient growth factors – particularly BDNF, inflammation, and gut microbial signaling.
Circadian rhythms
Our bodies have a natural 24-hour cycle of biological, hormonal, and behavioural patterns which help modulate a large portion of our physiological processes.
These include the production of our hormones that regulate sleep, hunger, metabolism, and mood.
Light and darkness play a crucial role in the brain’s circadian rhythm and brain health.
Being outside for 30 minutes each day, before the sun is overhead or 11 AM, for 30 minutes a day is a great natural way to synchronize your brain clock with the outside world.
It can help with resetting your biological clock.
If your sun reaches your eyes soon after waking, it triggers a neural circuit that controls the timing of cortisol and melatonin, which affects your sleep.
It doesn’t matter if you’re a night owl or early bird, Andrew Huberman suggests getting some sun for at least a few minutes after getting out of bed.
Getting outside for the light is better than sitting by a window because the glass filters out some of the UV light that assists in clock setting – the same thing for sunglasses.
Roughly between 10 and 40% of our gene expression in mammals is under circadian control, which includes our brains, liver, and muscles.
Circadian rhythms may have a large implication for our mental health and mood – like depression.
External cues are able to provide the body’s internal clocks to regulate behavioural, hormonal, and biochemical processes.
Food intake and light exposure are the most powerful ways to do this.
Alterations to these cues, whether it’s shift work, late-night eating, or other variations from normal day to night cycles of activities may have a deleterious effect on our health.
Let’s look at an example with light exposure.
We know that light directly influences the production of melatonin, a hormone that regulates the body’s response to darkness and influences our mood.
People who experience seasonal affective disorder (SAD), show significant improvement following the administration of melatonin.
People who have depression often exhibit cyclical patterns of their depression symptoms and they are typically more severe in the morning hours.
Genetic predisposition
Genetic factors contribute to a person’s susceptibility to depression.
A meta-analysis that investigated the genetic epidemiology of depression indicates that roughly 33% to 50% of the risk of developing depression is due to genetic influences.
But epigenetic factors, such as early life trauma, parenting styles, socioeconomic status, and others – also play a role.
Each of these exposures and genetic predispositions is unique to each individual, suggesting that depression is likely due to the gene-environment interactions.
Another meta-analysis looked at more than 800,000 people from three large genome-wide association studies of depression identified 269 genes, 102 variants, and 15 gene sets that were associated with depression – some of them had an influence on synaptic structure and neurotransmission.
We know that circadian rhythms and genetic factors are intrinsically linked.
The NPAS2 gene encodes the protein NPAS2, which functions in the brain as a generator and a maintainer of the circadian rhythm.
It comes from the same gene as the CLOCK gene, which encodes for the protein Clock, a key player of circadian rhythms.
If the Clock gene is absent, the production of Npas2 increases to main rhythms in the suprachiasmatic nucleus, your master regulator of circadian rhythms.
Mice that lack the NPAS2 gene exhibit sleep disturbances.
There was a study that looked at 500 Spanish adults who carried the two G alleles for NPAS2 gene had a 2.88-fold increase risk of major depression or bipolar disorders. The ones that carried only one of the alleles experienced a similar effect but only 1.44-fold increase risk.
We also know that jet lag may trigger a manic episode if you travel from east to west.
Check your genetics to see if you’re predisposed to different genes with 23andme
Pharmaceuticals and medications
We often hear that depression is a side effect of many prescription drugs.
A few of the drugs include:
- isotretinoin (Accutane – an anti-acne drug)
- varenicline (commonly known as Chantix®, a smoking-cessation drug)
- rimonabant and taranabant (anti-obesity drugs)
- many classes of cardiovascular drugs, including beta-blockers, calcium channel blockers, and angiotensin II inhibitors.
Cardiovascular drugs are commonly prescribed for older adults, and with the widespread practice of polypharmacy among older adults, they’re at greater risk of developing depression
Gut bacterial changes
We have a bidirectional signaling pathway between the gastrointestinal tract and the nervous system, also known as the “gut-brain” axis, which is a critical component of mental health.
Gut microbiome diversity has been strongly associated with mood-relating behaviours, including major depressive disorder.
This association stems from the recently characterized bi-directional communication system between the gut and the brain, mediated by neuroimmune, neuroendocrine, and sensory neural pathways.
We have tens of trillions of bacteria, viruses, and fungi that comprise our intestinal microbiota. Stress, sleep, diet, and mood can work together or independently to influence the gut microbial population, promoting diversity or dysbiosis.
Dysbiosis is a reduction in microbial diversity and a combination of the loss of beneficial bacteria.
Dysbiosis or a low diversity of gut microbes contribute to altered immune function, changed appetite and metabolism, and mood changes.
Our gut bacteria may also play a large role in our food cravings, especially sweets and chocolate.
With the influence of our dietary choices, they also have an influence on which microbes survive.
If you don’t feed the beneficial bacteria, they can’t grow or thrive in the environment.
Our standard western diet, which is high in processed foods, refined sugars, saturated foods, and vegetable oils, promotes the problematic bacteria population that activates the body’s immune system.
The cycle of poor stress management, dietary choices, and immune responses sets the stage for a vicious cycle of systemic inflammation and low mood.
Nutrition | The missing biological link
We know that our bodies need certain nutrients to survive and having all of them in the right amounts can allow us to thrive but research demonstrates that people with depression are often deficient in several key nutrients.
These nutrients are needed and involved in modulating inflammation, neurogenesis, and different aspects of metabolism.
The key nutrients that depressed patients present with are
There was also a cohort study of almost 14,000 people who looked at micronutrient adequacy and depression risk.
They found that micronutrient inadequacy in four or more micronutrients could exert a moderate role in the development of depression.
Depressed people often exhibit unhealthy dietary patterns, such as skipping meals, “emotional eating, preferential consumption of sweet, snack, or fast foods, and poor or excessive appetite.
Some of these behaviours are likely due to derangements to brain functions.
For example, depression-related loss of appetite is associated with the lack of ability to perceive sensations from inside the body ( like hunger).
Depression-related increases in appetite are associated with hyperactivity in the brains’ reward circuits.
There have been multiple studies that found low serum zinc in people with depression.
The association between the level of zinc deficiency and treatment-resistant depression appear directly linked to the severity of depressive symptoms
Zinc supplementation in combination with a selective serotonin reuptake inhibitor (SSRI) or a tricyclic antidepressant significantly improved symptoms of depression.
Zinc combined with a multivitamin has been shown to reduce anger and depression in young women compared to just the multivitamin alone
Yes, there is a genetic portion to the cause of depression. A meta-analysis that investigated the genetic cause of depression indicates that roughly 33% to 50% of the risk of developing depression is due to genetic influences.
There may be genetic and epigenetic factors that may predispose you to develop depression but it’s not the only reason. Using epigenetic (changes to your diet/lifestyle/beliefs for example) can alleviate or not allow the genetic changes to happen
Yes, we fully believe depression is curable. It’s important to find the right doctor and health care provider to create a treatment plan for you. Early diagnosis and prevention can alleviate depression
The suggestion that depression is caused by a chemical imbalance is a myth, there is limited to no science supporting this. Depression is caused by many factors which include trauma, diet, lifestyle, genetics, and inflammation.
According to the Canada Revenue Agency, depression is a disability if you are “markedly restricted in at least one of the basic activities of daily living” for a prolonged period of time, at least 12 months of almost constant impairment.
There is a link between depression and chronic pain. We suggest that you look into inflammation, trauma, and gut bacterial changes as there is an overlap in both cases
