A Case of the Blues? What causes Depression?

Vanessa Kam

I felt dubious about seasonal depression until I moved to England.  Can cold, dark winters really dampen our spirits?  I thought I was immune to these effects until December drew nigh and daylight slumped by 4pm…

 While a number of cross-sectional studies have cast doubt on the existence of seasonal depression, (wittily termed SAD–seasonal effective disorder), the abundance of media coverage on this phenomenon echoes the general ‘down in the dumps’ mood many endure at certain times of the year.  But when does occasionally feeling blue, part of the human condition, toe the line of depression, a debilitating mood disorder?

 With depression being a major risk factor for suicide and suicide among the leading causes of death worldwide, in recognition of National Suicide Prevention Day, we explore what morphs the mind into a ‘bad neighbourhood’.

What is depression?

Clinically, ‘depression’ encompasses several disorders where patients are absorbed by feelings of sadness, emptiness or irritability, with physical and mental changes which impair everyday functioning.

Major depressive disorder, put simply as depression, is the most common form.  In its manual, the American Psychiatric Association requires the following symptoms to be consistently present for a minimum of two weeks:

Depressed individuals have been shown to possess altered thought processes, falling into subconscious negative self-representations reinforced by biases in attention and memory to negative stimuli.  A key cognitive feature of depression is rumination, with sufferers repeatedly mulling over the causes and consequences of their current state.

Laboratory tests to diagnose depression do not exist, hinting towards a murky understanding of its pathophysiology.  Yet as the second leading cause of disability worldwide, it remains a major global health issue, affecting more than 300 million people.  In England, depression is the most common mental illness, with one in five of 5,450 respondents in a national survey having been diagnosed in 2014, and an estimated £10.96 billion cost to the country in 2010.

Considering its detriment to society and the individual, what is known about the underlying cause of depression?  Is there a single cause?

Causes of depression

The NHS webpage on causes of clinical depression kicks off by saying “There’s no single cause of depression”.

Well, that was easy.

Instead, a combination of biological, psychological and social factors intertwine for each individual, elegantly demonstrated by the diathesis-stress model.

This considers a person’s vulnerability or predisposition (diathesis) alongside both internal or external stresses in precipitating a depressive episode.  Those with a high diathesis require a lower stress level to stimulate depression, while the less-inclined cope with more setbacks.

But what might make someone a severe “diasthetic”?

Genetic components play a role.  Depression has a heritability of about 40%, meaning 40% of the variation in vulnerability amongst individuals is down to differences in genes.  This is comparable to type 2 diabetes, another common illness riddled with lifestyle and genetic factors, but lower than schizophrenia, which has a heritability of about 80%.

Despite this genetic contribution, genome-wide association studies (GWAS) have repeatedly failed to find significant gene variants associated with depression.  One study combed through the genes of 9,240 patients and 9,520 controls–the largest study as of 2012–and came out empty-handed.  Considering the success of GWAS in many other complex human diseases and traits, this points towards an exceptional heterogeneity within depression.

One study which found the tip of the iceberg included subjects with recurrent depression only.  By scrutinising 5,300 Chinese women who suffered repeated bouts of depression, two loci were finally identified.

 Intriguingly, one lies close to a gene required for making mitochondria, in line with recent hypotheses involving mitochondrial dysfunction in depression and findings of increased mitochondrial DNA with increased life adversities in depressed individuals.

 In fact several early life experiences contribute to diathesis.  Childhood abuse is plain to see, but even growing up in a negative environment with constant criticism, rejection or a depressed parent can mould the negative cognitive processes associated with depression.

Personality, largely a product of genetics and early life experiences, also ties in to depression.  A study of female twins over time found neuroticism, a personality trait characterised by moodiness, irritability, anxiety and self-consciousness, to mediate symptoms of anxiety and depression, perhaps due to a common negative bias in information-processing.  More alluringly, researchers have come to view depressed, neurotic individuals as active contributors in snowballing their afflictions, interacting with others in stress-generating ways.

With a foundational vulnerability, what about stress?  What factors may push individuals above the threshold?

Below are some common examples, from major adverse experiences like the loss of a loved one, to cumulative, minor chronic stresses like living with many toddler children.

Of most clinical relevance is co-morbidity.  Those who suffer from chronic physical diseases have higher rates of depression, leading to worse outcomes and significant healthcare costs.  A 2012 report estimated that £1 in every £8 the NHS spent on long-term conditions is linked to poor mental health, pointing towards a need for more holistic attention towards patient health.

But how exactly does stress invite depression?  The prevailing model taught to this day is the monoamine hypothesis, the idea that a chemical imbalance, the depletion of serotonin, noradrenaline and/or dopamine in the central nervous system, produces depressive symptoms.  Indefinite exposure to cortisol in chronic stress increases enzymatic breakdown of these neurotransmitters.  The hypothesis stems from the action of antidepressants like Prozac, which increases the availability of serotonin outside cells to act at synapses.

Yet mounting bad press uncovering the buried data, skewed positives, exaggerated efficacy and hidden harms of antidepressants adds to the list of limitations to this model.  An analysis of 70 trials found suicide ideation and aggression doubled for children and teens on certain antidepressants, an eery finding considering the unadulterated symptoms of depression itself.

As such, researchers are looking into inflammation, cell death in certain brain regions–depressed individuals have smaller hippocampi–and reductions in the already limited generation of neurons in the adult brain, all of which can be linked to chronic stress, as causes.  In the case of depression, despite the phrase being banned in the BMJ, more research is needed.

For the sake of current sufferers and the many to come.

#MentalHealth #VanessaKam