The Many Possible Causes of Depression

Depression keeps turning out to be more complicated the more closely researchers look at it. On the surface it shows up as a cluster of symptoms, but the machinery behind those symptoms is anything but uniform. Current work points to a long list of possible contributors: brain regions that are underdeveloped or just not working well, low levels of neurotransmitters, the way certain genes get expressed, a person's basic temperament, stress and the chemistry that comes with it, losing someone close early in life, trauma, physical illness, a biological clock that has slipped out of sync, and reactions to medication.

What makes treatment hard is that these rarely act alone. Two or three of them can braid together into a single person's depression, so the thing you are trying to treat has more than one root. The hope among researchers is that enough data will eventually let doctors tailor treatment to the particular mix driving each case.

Brain imaging has changed what is possible here. Being able to watch the nervous system at work, structure by structure, has let scientists map which regions handle mood, memory, the senses, and speech, and from there make educated guesses about which regions feed into depression.

Work published in The Journal of Neuroscience found a smaller hippocampus in some depressed people, along with reduced production of new neurons in that area. That finding offers one explanation for why antidepressants take weeks to kick in: they saturate the brain with neurotransmitters that, over time, prompt new neurons to form. The suggestion is that the shortage of neurons may matter more than the shortage of neurotransmitters. A 2003 study in Science lent weight to this. When researchers blocked neuron growth in animals, antidepressants stopped improving mood.

None of that erases the role of neurotransmitters. Research still shows that if the link between neurotransmitters and neurons gets disrupted or severed, depression can follow. Different neurotransmitters do different jobs; a lot of them govern mood, sleep, and blood pressure, which ties them to anxiety as well. When the signals that tell a neuron to release or withhold a given neurotransmitter misfire, the body produces physiological responses that drag on mood.

Genes are part of the picture too. Specific genes regulate mood and are constantly switching on and off to keep the body running smoothly. In someone who is genetically predisposed, a stressful stretch of life can throw off that rhythm, activating the wrong genes at the wrong moment and pulling mood down with it. Certain gene markers also turn up repeatedly in depressed people, which is a large part of why mood disorders tend to cluster in families.

Genes are not the whole story, though. Plenty of cognitive psychologists argue that temperament carries nearly as much weight. Over time we build up ideas about how the world works, and those ideas shape the expectations we fall back on under pressure. A temperament tilted a certain way can tip someone into depression. The encouraging flip side: temperament seems learnable, and shifting a person's worldview can ease the condition.

Stress tends to act as an accelerant rather than a lone cause. It does not make everyone depressed, but in people already vulnerable it piles on and can deepen the problem. The chemistry probably explains why. Under stress the body releases cortisol as part of the fight-or-flight response, and cortisol works alongside the brain's neurotransmitters. If something is off in how cortisol gets produced or released, it can throw off the supply and the usefulness of neurotransmitters, opening the door to anxiety and depression.

Early loss and trauma leave a long shadow. Losing someone you love when you are young, or living through abuse, raises the odds of depression later in adulthood. The thinking is that these experiences cause lasting changes in how the brain functions, leaving a person primed for depression. A study in the Journal of the American Medical Association found that women who had been abused as children showed stronger stress responses and higher stress-hormone levels during stressful tasks than women with no such history.

A range of medical conditions can bring on depression as well. Thyroid trouble is a familiar example, with an overactive thyroid pushing toward mania and an underactive one toward depression. Heart disease, stroke, endocrine disorders, cancer, and degenerative neurological diseases like Parkinson's and Alzheimer's have all been connected to depression. When depression grows out of a physical illness there is at least this comfort: treat the underlying condition and the depression often lifts along with it.

Hormones and the body's internal clock figure in too, especially with seasonal affective disorder. The circadian rhythm is what tells us when to sleep and wake, and when melatonin is produced in the wrong amounts or released at the wrong time, mood can sag into depression. For the people this affects, it usually hits in winter.

Then there are the medications themselves. Depression sometimes shows up as a side effect of prescriptions, including some antimicrobials, antibiotics, antifungals, and antivirals, certain heart and blood pressure drugs, hormones, sedatives, and sleep medications. Researchers do not fully agree on this, though. They argue over whether these drugs really contribute to depression at all and, if they do, how much.

Every new round of research widens what we understand about depression and, at the same time, opens fresh questions. The disorder is proving to be a tangle of factors that combine differently in different people, which is exactly what makes finding the right treatment for any one person so difficult. The payoff of better science, if it comes, will be treatment matched to the individual and results that hold up.

- Tina Fuster