Depression is not a chemical imbalance

Depression is not a chemical imbalance–that’s what the best data on the subject suggests.

Now please don’t misunderstand me. I believe that major depressive disorder is inherently biological. I just remain unconvinced that brain chemistry alone tells us much about depression. At it’s best, the “chemical imbalance hypothesis of depression” is an outdated theory. More cynical observers might say that it’s an oversold marketing message.

The belief that depression is a chemical imbalance comes from a misunderstanding of the monoamine theory of depression. According to this theory, depression is caused by dysfunction in one of the monoamine neurotransmitter systems. These neurotransmitters–serotonin, norepinephrine, and dopamine–are certainly related to mood, but changing the absolute levels of these chemicals in the brain has not been consistently shown to affect mood. Correlation (as I’m sure you’ve heard) isn’t causation.

The most convincing argument against the chemical imbalance hypothesis comes from clinical research into antidepressants. The most commonly prescribed antidepressants are the selective serotonin reuptake inhibitors, also known as the SSRIs. Within hours of taking these drugs, the effective level of serotonin is increased at every serotonin-containing synapse in the brain. But unfortunately, patients who take SSRIs feel no better than patients taking placebo for at least 2 weeks (and realistically, it takes most people 4-6 weeks to really start feeling any effect at all). If depression was caused by a simple chemical imbalance, we’d expect a much more rapid response. And this long time to effect happens with all FDA approved antidepressants, regardless of their action on the serotonin, norepinephrine, or dopamine systems. (I’ve heard some well-meaning doctors tell their patients that the drugs take 4-6 weeks to reach a significant dose in the bloodstream. However, the vastly different half-lives of these drugs and the remarkable consistency in their time to effect argues strongly against this explanation.)

So what causes depression? Depression seems to be related to dysfunctional brain circuitry. A depressed person may very well have problems with one of the monoamine neurotransmitter systems, but it is the system that is impaired, not necessarily the chemical concentration. For recovery to occur, neurons in the brain must find a way to appropriately reconnect with each other.

Thankfully, the brain is remarkably resilient. While as many as 20-40% of the population will experience at least one episode of major depressive disorder, a surprising number recover without any treatment. This isn’t to say that treatment doesn’t work (it does) or that the risk of untreated depression is trivial (it isn’t). It’s just to point out that the brain has mechanisms in place to rebuild dysfunctional synapses. And if you really want to kickstart recover, every known treatment for depression has been shown to increase the levels of neuronal growth factors. The most well known of these factors is brain-derived neurotrophic factor (BDNF), and it is increased by antidepressants, talk therapies, electroconvulsive therapy, and even experimental treatments like ketamine. However, the diverse targets of these therapies may trigger growth in different regions in the brain, which could explain why certain people respond better to one treatment than another. In most cases, the best initial treatment is a combination of antidepressants and cognitive-behavioral therapy.

Why does it matter that we stop talking about depression as a chemical imbalance? For one, an accurate understanding of science matters. When you realize that depression is caused by impaired brain circuitry, it makes sense that depression arises from a combination of genetic, environmental, and psychological factors. On a more human level, calling depression a chemical imbalance trivializes the disorder. A chemical imbalance sounds like something that can be rapidly reversed. It makes us think that there is a magic pill that can quickly fix things. It’s the biological equivalent of the words “why can’t you just snap out of it.” Overcoming depression–especially severe depression–takes time and appropriate treatment. Finally, thinking of depression as a problem with circuitry helps us conceptualize depression as a complex set of disorders with unique causes, manifestations, and treatments. It gives us a reason to approach all sufferers as individuals that cannot be treated with a one-size-fits-all approach.

This model of depression isn’t perfect, and my explanation is, of course, a gross oversimplification. But when we recognize that depression is a circuit problem, it enables us to take some responsibility for rebuilding and maintaining the circuitry that brings us happiness. This is what cognitive-behavioral therapists have been telling us all along. By learning how to combat the thought and behavior patterns that worsen depression, you can help yourself rebuild the faulty circuits within your own head. Conquering depression often takes the help of competent professionals, but recovery without learning to help yourself is almost impossible.

  • Anonymous

    Interesting take but I fear your post comes across as taking dysfunctional brain circuitry as the end all be all of depression when I don’t believe we can simply say it comes down to a pure circuit problem. There is ample evidence for the action of serotonin on 5-HT1A receptors and interplay with autoreceptors in clueing into the delayed response to SSRI/SNRI/5-HT1A receptor agonists in some patients. I also think you leave out a vast number of additional models based on significant scientific merit (analytic rumination hypothesis or the behavioral shutdown model for example) which suggest none of this is abnormal, rather the evolutionary sequelae of a modern society barraging us with complex inter and intra personal problems amid physical, emotional, and psychological stress. Labeling the circuitry as dysfunctional may also be misleading. Yes, there is evidence of plasticity and cortical thickening, but the interplay between 5-HT1A receptor stimulation and BDGF doesn’t simply lead to the conclusion that there is something wrong with the circuitry or the circuitry needs to be fixed. Some studies even show an increase risk for treatment resistant depression when you have these increased levels of BDGF. It is too early to completely dismiss the chemical imbalance model entirely and too early to bet it all on circuitry. That said, I still applaud the effort to help educate and inform as you make a number of worthwhile points many do not know or think about regularly. Thank you.

    • Jeff

      Thanks for your input! When writing this post, I realized that the biggest challenge would be explaining my understanding without providing so much detail that it would turn off the lay reader. I personally don’t think that depression is a single entity, and so any particular explanation is bound to have some holes in it. I agree that there are many other avenues to explore and so much that we do not know. However, I believe that thinking about depression as a problem of circuitry is the most compelling broad interpretation of the data we yet have. Although it can’t explain everything, it certainly provides an interesting framework on which further hypotheses can be tested. I appreciate the time you took to point out what some alternative explanations might be! I’m always open to having my mind changed, and if it can be done with solid data, so much the better.

  • Joshua Lawyer

    Hi Jeff. Any evidence that juggling contributes to or alleviates depression? I have heard that it increases gray matter in the brain. Could site swap be the answer to faulty synapses? Could no-spin backcrosses lead to tardive dyskenesia? Can Jason do something else with his hair? Can the voices in my head please stop arguing over who is going to win the next wjf freestyle competition?

    • Jeff

      Now those are questions I wish I had answers to! :)

  • Lish Troha

    Jeff, this is awesome. SO LEGIT. Thank you for your courage in speaking out against the mainstream theory. Please see my blog and let me know what you think:

    Keep up the good work!

    • Jeff

      Thanks for the kind words. I appreciate your blog post. I do think of major depressive disorder as something that should receive clinical attention. However, I’m skeptical of any approach that uses psychopharmacology alone (and I think just about every well-informed psychiatrist is too). My next post will likely be on what I would consider to be the ideal approach to the treatment of depression. Stay tuned!

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