Thinking Beyond the ‘Chemical Imbalance’ Theory of Depression

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What if everything we think we know about depression is wrong? That’s the contention of journalist and writer Johann Hari in his latest book, Lost Connections, which was recently excerpted on the Guardian’s website. Maybe you saw it — it was extremely popular and widely shared online.

Unfortunately, there are numerous problems with the piece, and many in the mental-health field — and some who deal with depression themselves — are seriously unhappy about it. Perhaps the most dangerous element is his persistent condemnation of antidepressants and their use, at one point describing them as essentially useless, with claims of their effectiveness being purely “marketing copy.” This is, at best, an alarming oversimplification of claims that aren’t widely accepted and based on questionable evidence. And this is deeply unhelpful. There is already plenty of stigma associated with taking antidepressants without Hari advancing the notion that they’re useless and ineffective, which just further undermines those who depend on them.

Still, Hari does make some valid points. It’s true, for instance, that antidepressants are overly relied upon and nowhere near as effective as many assume or hope. It’s also fair to say that lifestyle changes, particularly radical ones, can be a big help with alleviating the experience of depression. And it’s accurate that depression is not just a matter of a “chemical imbalance” in the brain, but instead is a combination of internal and external factors, from a person’s genes to their environment.

It’s that last point in particular that seemed to strike a chord with readers. The idea that lifestyle and genetic factors all contribute to mental-health problems isn’t a new one, despite Hari framing it as such in his piece. It’s known as the biopsychosocial model, which was established in the ’70s and has been taught to students for at least 20 years now. The problems and limitations of antidepressants and the “chemical balance” theory have been highlighted and debated since the turn of the millennium. But the fact that this point is what so many readers responded to makes it worth discussing, as it highlights the unappreciated complexity of antidepressants, and the disorder they are intended to treat.

Because the truth about antidepressants is a lot more complicated than most people realize. It’s true that some people don’t benefit from antidepressants at all. Others can’t do without them. They aren’t some magic bullet cure-all, but neither are they some sinister moneymaking scheme perpetuated by shady pharmaceutical companies and uncaring professionals.

As Hari points out, antidepressants were discovered by accident, by Swiss scientists looking for treatments for schizophrenia in the 1950s. It may seem bizarre, but a lot of drugs were discovered by accident. Who’s to say that without Alexander Fleming’s lackluster approach to laboratory cleanliness we’d have ever discovered antibiotics? Flash forward to today, and there are now several types of antidepressants available, from the earliest tricyclics and monoamine oxidase inhibitors to the ubiquitous modern-day selective serotonin reuptake inhibitors (SSRIs). One thing that links them all is that they “work” by increasing the amount of neurotransmitters, the chemicals that allow brain cells to communicate with each other across the synapse in order to make things happen, available in the brain. They usually do this by preventing the breakdown or removal of neurotransmitters that have already been used, so they hang around longer and keep having an effect, sort of like putting the used coffee grounds back in the filter, to squeeze a few more cups out of them.

The action of antidepressants is closely tied to the monoamine theory of depression, which is the technical term for all those references to “chemical imbalances in the brain” that supposedly underpin depression. The logic is fairly straightforward: Antidepressants improve mood, and their mode of action is to raise the levels of certain neurotransmitters, like serotonin and dopamine (chemically classed as monoamine transmitters, hence the name). Therefore, a deficiency or absence of monoamine transmitters must be a key factor in depression. Makes sense, right?

Sadly, the human brain being as complex and messy as it is, nothing is ever that neat, and in recent years the monoamine theory, while once widely accepted, has fallen further out of favor. One main argument against it is the fact that antidepressants, thanks to the rapid action of the human brain and metabolism, increase neurotransmitter levels pretty much right away. However, the therapeutic effects don’t appear for several weeks. What should be like flicking a light switch is more like turning a cruise ship, a long and ponderous affair with a lot of hazards involved. Add to this the fact that many people simply don’t respond to these antidepressants, and that other medications which work via very different mechanisms may work for some people, and it’s clear that the monoamine theory, while it may be a part of it, is not the whole story.

There are other possible factors to consider. Antidepressants, for instance, are also known to increase neuroplasticity, the ability of neurons to change and adapt to what’s asked of them, and something that’s impaired in people with depression. Maybe a more static, rigid brain underlies depression? Another interesting focus is on the role of inflammation, which is believed to cause excess stress on the brain’s structure, leading to depression. The chemical histamine, which regulates much of the inflammatory response, is also a monoamine, so perhaps there’s a link there too?

None of this really addresses how these underlying biological factors come about, of course. It could be genetic, it could be physiological, it could be undue stress caused by unpleasant life events. The brain, for all its fabulous complexity, is still a biological organ, as vulnerable to whatever the world throws at is as any other. The skull may protect it from direct injury, but blunt-force trauma isn’t the only thing that can upset the brain’s functioning.

It’s the complexity and endless variability of the human brain that is at the root of many of the problems surrounding depression. It would be great if a problem or malady afflicting the brain could be solved by swallowing a few capsules, but that’s obscenely optimistic to say the least. There’s so much going on the brain at any given time that a blunt, blanket approach like “raising the levels of certain chemicals” has essentially no hope of having the same beneficial effects for everyone. So much does the brain vary from person to person that it is to be expected that antidepressants will do nothing for some and be literally lifesaving for others, and every variation in between.

There are reasons to be wary of the reliance on antidepressants, of course. They aren’t a blanket forever-effective cure-all by any means. Some argue that they’re no more effective than a placebo, but a closer look at the evidence underlying this suggests they’re not substantially more effective than placebo, which is a different thing. If you’re in the grips of depression, an improvement is still helpful, even if it’s not a complete fix. It’s an ongoing argument in the scientific arena, but even a slight boost in your mood can mean the difference between getting things done and remaining trapped under the weight of your own despair.

Perhaps the real problem underlying all this is that there’s no easy solution or “quick fix” for depression. This is usually the case for any ailment, but the fact that antidepressants have become so commonplace perhaps gives the impression that there is, and this is wrong. It would be naïve to deny that the involvement of wealthy drug companies that profit from their use is a big factor in all this, but, like depression and the action of antidepressants themselves, it’s a situation that can’t be limited to a simple, straightforward solution.

Antidepressants are, all things being equal, just another weapon in the still-expanding arsenal available to us in the battle against depression. And because of the way humans and their brains work, it’s invariably a battle people have to fight in their own unique ways. Condemning others for their choices when it comes to tackling their own demons is an approach that helps nobody.

Dean Burnett is a neuroscientist and author of Idiot Brain. His next book, Happy Brain, is out in May.

Moving Beyond the ‘Chemical Imbalance’ Theory of Depression