We’ve all heard of the “chemical imbalance” explanation for mental illness. This terminology has served a purpose in making the argument that mental illness is actually an illness. However, it is a gross simplification of mental illness in terms of what’s actually going on in the brain. Lately I’ve read criticism of the chemical imbalance idea as being inaccurate, which makes me wonder if it’s terminology that’s no longer serving us. I’m going to focus on depression, as it’s probably the condition for which I’ve seen the chemical imbalance idea challenged the most.
This chemical imbalance theory arose in the 1960’s, when it was hypothesized that a deficit in serotonin caused depression. According to Wikipedia, it began with observations with the drugs reserpine and isoniazid, and the way they affected monoamine neurotransmitters (the monoamines include serotonin, norepinephrine, and dopamine). The serotonin hypothesis fuelled further research and the development of new serotonergic drugs. These drugs proved to be effective, which reinforced the hypothesis. “Chemical imbalance” certainly captures the state of scientific understanding 50 years ago, but we’ve come a long way since then.
Now it’s generally recognized that the etiology of depression is complex and multi-factorial, and the idea of a simple serotonin deficit is inaccurate. In many ways, the more the science has progressed the more we realize just how much we don’t know. A few of the biological factors that have been implicated are:
- Signalling between neurons via monoamine neurotransmitters (serotonin, norepinephrine, and dopamine): This is much more complex than absolute amounts of these neurotransmitters. Regulation of neurotransmitter receptors and transporters on nerve cell membranes has a major impact on signal conduction. It’s been suggested that the delayed onset of action of antidepressants may be related to the time it takes to adapt the regulation of these receptors via changes in the expression of genes encoding for them.
- Glutamate: It is thought that the neurotransmitter glutamate can cause what’s referred to as “excitotoxicity”. Inflammation is one of the factors suspected to play a role in promoting glutamate excitotoxicity, mediated by various factors including microglial cells. Ketamine affects the glutamate signalling system via its effect on NMDA receptors.
- Genetic factors: Genetic variants affecting such things as serotonin transporters and methylation processes are thought to potentially play a role. Variants in the SERT (serotonin transporter) gene are associated with different patterns of response to treatment than those with the “normal” SERT gene. Significantly more research is needed in this area to gain a greater understanding of the role of genetics.
- Epigenetic changes: Epigenetics refers to when and how often our genes are translated into the proteins that they code for. A wide variety of environmental factors are thought to affect this, and this is where adverse childhood experiences can have a huge impact. There is still much, much more to be learned in this area.
Sometimes people will argue that depression is not biologically caused, but instead is caused by psychosocial factors including trauma. I guess the problem I have with this is that it strikes me as another oversimplification of mental illness. David Karp is a remarkable author and sociologist who has written about his own experiences with depression. He argues that purely social determinism is just as problematic as biological determinism when it comes to depression.
I’m inclined to think that at this stage of the game “chemical imbalance” has outlived its usefulness. In a time when it’s so easy for people to look things up, if we’re using terminology that oversimplifies to the point that it’s not really accurate, we may just be shooting ourselves in the foot by hanging onto this kind of language. I’m not sure what would work better. I could suggest “complex, multifactorial, biopsychosocial illness” but that’s rather long-winded.
What do you think is the best way to characterize mental illness?
Note: There are a couple of good papers by Albert and Benkelfat looking at where things stand now in relation to the serotonin deficit hypothesis; these are available from the National Institutes of Health here and here.