The Harvard Medical School:

It’s often said that depression results from a chemical imbalance, but that figure of speech doesn’t capture how complex the disease is. Research suggests that depression doesn’t spring from simply having too much or too little of certain brain chemicals. Rather, depression has many possible causes, including faulty mood regulation by the brain, genetic vulnerability, stressful life events, medications, and medical problems. It’s believed that several of these forces interact to bring on depression.

To be sure, chemicals are involved in this process, but it is not a simple matter of one chemical being too low and another too high. Rather, many chemicals are involved, working both inside and outside nerve cells. There are millions, even billions, of chemical reactions that make up the dynamic system that is responsible for your mood, perceptions, and how you experience life.

With this level of complexity, you can see how two people might have similar symptoms of depression, but the problem on the inside, and therefore what treatments will work best, may be entirely different.

Researchers have learned much about the biology of depression. They’ve identified genes that make individuals more vulnerable to low moods and influence how an individual responds to drug therapy. One day, these discoveries should lead to better, more individualized treatment (see “From the lab to your medicine cabinet”), but that is likely to be years away. And while researchers know more now than ever before about how the brain regulates mood, their understanding of the biology of depression is far from complete.

What follows is an overview of the current understanding of the major factors believed to play a role in depression.

Harvard does a great job of exploring and explaining the thought process behind the major factors they list. Even so, the answer to the title question remains, we just do not know.

I recommend this video: Charlie Rose Brain Series 2: Depression http://www.charlierose.com/view/interview/12380

Then there is: Glia: The Unsung Heroes of the Brain http://theairspace.net/science/glia-...s-of-the-brain/

Did you know that neurons aren’t the only kind of brain cell? In fact, these celebrated biological information processors only comprise 10% of the cell population of the brain. The other 90% of brain cells, called glial cells or glia, don’t have as many “intelligent” characteristics as their complex neuronal cousins, but the nervous system wouldn’t be able to function without them. Up until recently, glia, whose name derives from the Greek word for glue, were written off by the scientific community as a simple, gelatinous substance whose sole purpose was to act as packing peanuts to cushion our precious neurons. With more advanced modern research methods, however, we are starting to recognize the subtle yet essential contributions that glia make to our cerebral performance.
***
Glia, specifically oligodendrocytes in the brain and Schwann cells in the peripheral nervous system, form and maintain the insulating myelin sheaths around neuronal axons. You can think of oligodendrocytes and Schwann cells as the electricians of the nervous system: the myelin sheath increases the conductivity of an action potential (the way that neurons communicate with each other) throughout the length of the axon so the signal can be transmitted efficiently to the next neuron and beyond, just as the coating of an electrical wire enriches the current flow throughout the wire. The oligodendrocytes and Schwann cells ensure that the correct axons are myelinated, and that the signals are efficiently reaching their intended destinations. Without myelin sheaths, many of our brain’s critical messages would fizzle out before reaching their intended destinations. Multiple sclerosis, a painful autoimmune disease that that severely impairs one’s motor skills and other important bodily functions, is the result of the systematic degeneration of one’s myelin sheaths. In other words, if your glia malfunction, your whole body malfunctions.

There is more about the role of glia, but to conclude:

Overall, glia are paramount members of the “society” of the nervous system. Their various contributions to cranial functioning are constantly being discovered, but we still don’t know the full extent of their capabilities and neural influences. It very well may be the case that glia play essential roles in the onset and/or cure for various psychological disorders, but neuroscientists will have to devote more time to researching them, which may be difficult when neurons seem so important and exciting. Despite the misinformed origins of their name, glia are truly the “glue” of the nervous system: their functions hold the entire system together, and without them, everything would surely fall apart.

While we do not know with exactitude what causes depression, I perceive we are gaining more familiarity at an accelerated rate.