Earlier this year, the World Health Organisation (WHO) listed depression as the leading cause of ill health and disability worldwide.
Not lung cancer, obesity or heart disease (on their own, individual fronts), but depression -- a common and serious mood disorder that, today, will reach one in seven Australians alone at some point in their lifetime.
Clinical depression is a life-threatening thing. It puts your life at risk, but it also kills the quality of your life. I believe Australians are some of the most aware people on Earth about it.Ian Hickie
It has not always been this way. The WHO's latest estimates show an 18 percent jump, globally, between 2005 and 2015. Yet despite advancements in modern neuroscience, we remain mystified by what causes it -- and why some are more vulnerable to it than others.
"Depression in itself has a very general description and it is not difficult to diagnose nor document in terms of the impairment caused on a person's life," Ian Hickie, Professor of Psychiatry and co-director of the Sydney Brain and Mind Centre told Huffpost Australia.
"But this is also an inherent challenge, as understanding the combination of factors that has caused the depression, in an individual case, and what is the best path for treatment is far from simple. In truth, there are still a lot of gaps."
Why cause matters
In simple terms, clinical depression is a mood disorder that can begin at any age, and manifest in different forms. Early-onset means the illness is observed in children, adolescence or young adulthood, while late-onset typically occurs in adults aged 65 years or older.
Like any illness, it comes down to a "syndromal diagnosis": low mood and/or loss of interest and pleasure in usual activities, as well as other symptoms, for at least two weeks.
"Saying someone has major depression is the same thing as saying someone has pneumonia or heart failure. We see the signs and symptoms," Hickie said.
"With pneumonia, your lungs may be inflamed or there may be fluid around them. You may have a fever, or an infection. Trying to work out the individual case to treat it is in part due to the problem, but it is also in part due to what is causing it."
In psychiatry, such syndromal diagnosis draws even more questions -- with arguably greater risks.
Misunderstanding lies with recognition of the syndrome, which leads to not treating the problem seriously. If you don't know what the specific cause or treatment is, how do you know that that is what you have?Professor Ian Hickie
"We are at a place in psychiatry -- where most physical health infections and diseases were at about fifty years ago -- where we are jumping from well recognised syndromes to much more specific causes and treatments," Hickie said.
"As brain science rapidly improves, the goal is to get highly personalised statements about the likely cause, and importantly, if you have it, how to treat it?
"Cause matters for treatment and for prevention. If you know things, you can do something about it."
Nature versus nurture
Beyond the syndromal diagnosis of major (or clinical) depression are a range of sub-types.
Perinatal depression is experienced by women before or leading up to pregnancy, whilst atypical depression, involves specific symptoms related to excessive sleepiness or fatigue, often raising its head in early years.
For each sub-type, there is a different pathway, paved by a combination of environmental, biological and genetic factors.
According to Hickie, this complex interplay can be understood using a 70 to 30 ratio.
"What we know from a range of family adoption and twin studies is that if you deal with the population as a whole, about 30 percent of the causation of these forms of depression is genetic. About 70 percent is possibly environmental, meaning anything that has happened to you, now or in childhood," Hickie said.
"These are well-replicated estimates, but they are just averages. What they don't tell you is the individual situation. In some families and in some settings, for example, it is likely that the genetic component is going to be much stronger."
We look at genetics in terms of how a person's genetic makeup interacts within an environment. It is not one or the other. Ian Hickie
This 'nature versus nurture' explanation has been etched into explanations of causation since the 1970s. But Hickie believes it is misunderstood.
"We look at genetics in terms of how a person's genetic makeup interacts within an environment. It is not one or the other," Hickie said.
"People sometimes think, rather blindly, that if you stop one risk factor, there would be no cases of depression. This is untrue. There is a vulnerability in humans to these disorders in certain environmental situations.
"Population-wise, we need to start focusing on reducing the environmental risks that we know well, promoting the protective factors -- which is really all about social cohesion -- and working towards using genetic coding to personalise treatment."
Take late onset depression, experienced by those aged 65 years and older, that has been strongly linked to cerebrovascular disease.
"In that area, treatment of the physical health risk factors -- reducing smoking, treating hypertension and managing lifestyle factors -- means the number of people with the condition, as a spin off, is going down," Hickie said.
But less progress, coupled with a rising incidence, is being made in early onset depression -- where there are several, less defined pathways.
Environmental factors in early onset depression
According to Hickie, about 50 percent of the cases of early onset depression are underpinned by childhood anxiety.
"Anxious kids become depressed teenagers," Hickie said.
"There are a series of changes that happen in puberty that transforms the situation from anxiety, to moodiness. Symptoms take off, particularly among 12 to 14-year-olds, and by 15 or 16, you see increasing rates of formal depressive disorders."
Without knowing the individual level of causation, changing one of the known pathways -- like childhood anxiety -- may effectively reduce the number of people who experience teenage depression.
Of these changes, some are undoubtedly hormonal.
"You see higher rates in girls of this age than boys, so there are clear biological processes going on, underpinned by hormonal and immune changes. But which girls get depressed in that particular period? We can't predict that."
A disturbed sleep/wake cycle
Links between sleep disturbance and depression are strong, with both the subjective experience of sleep symptoms and changes to sleep architecture being well documented.
Beyond anxiety, approximately 30 percent of cases can be explained by a disturbed sleep/wake cycle -- a symptom of atypical depression among teens. This is also known as hypersomnia.
"The sleep cycle changes extensively during adolescence. While primary kids go to sleep with the sun and wake with the sun, teenagers will begin to shift their body clock later and later, tending to rise much later," Hickie said.
"A disrupted cycle is characterised less by moodiness and more by tiredness, low energy and fatigue. In more severe cases, this can turn into atypical depression."
Brain developmental problems
According to Hickie, this is the third most common pathway.
"If a child has an abnormality in brain development early in life, their chances of getting depressed later on increases," Hickie said.
There are some complex brain and social reasonings behind this.
"Those kids with ADHD or autistic disorders are more likely to have had school difficulties, experienced failure or bullying -- on top of the brain impairment," Hickie said.
And while each pathway offers an opportunity for recognition and prevention in childhood, they are usually not addressed.
"The problem hits the wall during adolescence, and it becomes commonly associated social isolation, troubles with peer relationships and poor performance. That's where the kids usually reach a point of tension -- through self harm, suicidal ideation and more obvious displays of stress," Hickie said.
"A lot of the boys also go on to abuse alcohol and drugs and coping mechanisms and you start to see secondary problems arising in their 20s."
Beyond common pathways, types of depression can also be triggered by a response to a distressing situation, like loss or stress.
Childhood sex abuse is a specific risk factor.
"Young girls have higher rates of exposure to sexual assault. We don't need to wait to find out who is most at risk to start reducing the risk factor in that situation," Hickie said.
Having a baby is another example. While two thirds of cases are found in women who were depressed before having their baby (antenatal depression), the illness is a new experience for one third of new mothers. This is tied to a range of environmental factors.
"This probably relates to a combination of hormonal insult plus big changes in sleep wake cycle. But if you are vulnerable to a disrupted sleep cycle, you may not find that out until you have your first baby," Hickie said.
Genetics, and moving forward
And then we come to genetics, accounting for approximately 30 percent of causation.
Types of depression can run in families, and some people will be at an increased genetic risk. But it is never inevitable.
You don't inevitably get depression. Even in cases where it is strongly genetic, there are still a large set of environmental factors at play.
"When it comes to genetics, you are dealing with a vulnerability, not an illness indicator in itself," Hickie said. "You don't inevitably get depression. Even in cases where it is strongly genetic, there are still a large set of environmental factors at play."
Hickie, along with researchers at the QIMR Berghofer Medical Research Institute, is currently leading the 'Australian Genetics of Depression Study' as part of a global collaboration designed to better detect genetic factors that contribute to clinical depression and its treatment.
The study requires a survey to be completed before volunteers, picked by researchers, submit a saliva DNA sample to generate their genetic code, known as a "genome wide association scan" (GWAS).
"What we already know from molecular genetic studies is that there are many genes that are contributing to forms of depression. There is not one common gene type at play for each type," Hickie said.
Each set of genes is predicted to sit on various known pathways -- some hormonal, others immune or related to the body clock.
"Where we want to go now is to work out what the variations in those common genes are and which pathways they are sitting on. That way we can distinguish the genetic variations that are operative in an individual's situation."
'What is the genetic variation in your hormone code that is driving your depression as a female adolescent?' We want to be able to answer that. Ian Hickie
"We have five or six common pathways. If we can put an individual largely on one or two of these pathways by measuring their genetic codes (and the variations within it), we are much more likely to provide the right treatment that has a high probability of being successful, and a low probability of causing untoward side effects or harm," Hickie said.
For Hickie, understanding genetic coding can be empowering.
"People can see better what has made them vulnerable," he said. "But on the flip side, some tend to feel that genetics, in some way, removes the blame.
"The issue with this area in particular is that people still are getting blamed for it, that they brought it on."
Aiming for involvement from 20,000 adults, 10,000 Australians have already began the process of survey completion, as of April 17.
"We're thrilled that so many Australians have been willing to be involved, and I think it tells you a lot about the experience," Hickie said.
"I encourage people to be involved in the discussion, and to look to your family. The more people who participate, the quicker we'll have the answers."
Lifeline is exploring Australia's suicide crisis with business and community leaders at the #StopSuicide Summit on May 1, in partnership with HuffPost Australia and Twitter Australia.
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